Aurora kinase modulators and method of use

ABSTRACT

The present invention relates to chemical compounds having a general formula I 
     
       
         
         
             
             
         
       
     
     wherein A 1-8 , D′, L 1 , L 2 , R 1 , R 6-8  and n are defined herein, and synthetic intermediates, which are capable of modulating various protein kinase receptor enzymes and, thereby, influencing various disease states and conditions related to the activities of such kinases. For example, the compounds are capable of modulating Aurora kinase thereby influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of Aurora kinase.

This divisional patent application claims the benefit of U.S. patentapplication Ser. No. 12/080,669 filed Apr. 3, 2008, which in turn claimsthe benefit of U.S. Provisional Application Ser. No. 60/922,205, filedApr. 5, 2007, both specifications of which are hereby incorporatedherein by reference in their entireties.

FIELD OF THE INVENTION

The invention relates to the field of pharmaceutical agents and, morespecifically, is directed to compounds and compositions useful formodulating Aurora kinase, and to uses and methods for managing cellproliferation and for treating cancer.

BACKGROUND OF THE INVENTION

Cancer is one of the most widespread diseases afflicting mankind and amajor cause of death worldwide. In an effort to find an effectivetreatment or a cure for one or more of the many different cancers, overthe last couple of decades, numerous groups have invested a tremendousamount of time, effort and financial resources. However, to date, of theavailable cancer treatments and therapies, only a few offer anyconsiderable degree of success.

Cancer is often characterized by unregulated cell proliferation. Damageto one or more genes, responsible for the cellular pathways, whichcontrol progress of proliferation through the cell cycle, typicallycauses the loss of normal regulation of cell proliferation. These genescode for various proteins, which participate in a cascade of events,including protein phosphorylation, leading to cell-cycling progressionand cell proliferation. Various kinase proteins have been identified,which play roles in the cell cycling cascade and in proteinphosphorylation in particular.

One class of proteins found to play a part in cell cycling and,therefore, cell proliferation is the Aurora kinase family of proteins.Aurora kinases are enzymes of the serine/threonine kinase family ofproteins, which play an important role in protein phosphorylation duringthe mitotic phase of the cell cycle. There are three known members ofthe Aurora kinase family, Aurora A, Aurora B and Aurora C, also commonlyreferred to as Aurora 2, Aurora 1, and Aurora 3, respectively.

The specific function of each Aurora kinase member in mammalian cellcycle has been studied. Aurora-A is localized to the centrosome duringinterphase and is important for centrosome maturation and to maintainseparation during spindle assembly. Aurora-B localizes to thekinetochore in the G2 phase of the cell cycle until metaphase, andrelocates to the midbody after anaphase. Aurora-C was thought tofunction only in meiosis, but more recently has been found to be moreclosely related to Aurora-B, showing some overlapping functions andsimilar localization patterns in mitosis. Each aurora kinase appears toshare a common structure, including a highly conserved catalytic domainand a very short N-terminal domain that varies in size. (See R. Giet andC. Prigent, J. Cell. Sci., 112:3591-3601 (1999)).

Aurora kinases appear to be viable targets for the treatment of cancer.Aurora kinases are overexpressed in various types of cancers, includingcolon, breast, lung, pancrease, prostate, bladder, head, neck, cervix,and ovarian cancers. The Aurora-A gene is part of an amplicon found in asubset of breast, colon, ovarian, liver, gastric and pancreatic tumors.Aurora-B has also been found to be overexpressed in most major tumortypes. Overexpression of Aurora-B in rodent fibroblasts inducestransformation, suggesting that Aurora-B is oncogenic. More recently,Aurora-B mRNA expression has been linked to chromosomal instability inhuman breast cancer. (Y. Miyoshi et al., Int. J. Cancer, 92:370-373(2001)).

Further, inhibition of one or more of the Aurora kinases by severalparties has been shown to inhibit cell proliferation and triggerapoptosis in several tumor cell lines. Particularly, inhibition ofAurora has been found to arrest cell cycling and promote programmed celldeath via apoptosis. Accordingly, there has been a strong interest infinding inhibitors of Aurora kinase proteins.

Thus, the inhibition of Aurora kinases has been regarded as a promisingapproach for the development of novel anti-cancer agents. For example,WO 04/039774 describes aza-quinazolinones for treating cancer viainhibiton of Aurora kinase, WO 04/037814 describes indazolinones fortreating cancer via inhibiton of Aurora-2 kinase, WO 04/016612 describes2, 6, 9-substituted purine derivatives for treating cancer via inhibitonof Aurora kinase, WO 04/000833 describes tri- and tetra-substitutedpyrimidine compounds useful for treating Aurora-meiated diseases, WO04/092607 describes crystals useful for screening, designing andevaluating compounds as agonists or antagonists of Aurora kinase andU.S. Pat. No. 6,919,338 and WO 03/055491 each describe substitutedquinazoline derivatives as inhibitors of Aurora-2 kinase.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a new class of compounds useful formodulating one or more of the Aurora kinase enzymes and for treatingAurora kinase-mediated conditions and/or diseases, including cancer. Inone embodiment of the invention, the compounds, includingpharmaceutically acceptable salts thereof, are generally defined byFormula I

wherein A¹⁻⁸, D′, L¹, L², R¹, R⁶⁻⁸ and n are defined herein.

In another embodiment, the invention provides compounds of Formulas II,III and IV, which are similar in structure to Formula I above.

The invention also provides processes for making compounds of FormulasI-IV, as well as intermediates useful in such processes.

The compounds provided by the invention have Aurora kinase modulatoryactivity and, in particular, Aurora kinase inhibitory activity. To thisend, the invention also provides the use of these compounds, as well aspharmaceutically acceptable salts thereof, in the preparation andmanufacture of a pharmaceutical composition or medicament fortherapeutic, prophylactic, acute or chronic treatment of Aurora kinasemediated diseases and disorders, including without limitation, cancer.Thus, the compounds of the invention are useful in the manufacture ofanti-cancer medicaments. For example, in one embodiment, the inventionprovides a pharmaceutical composition (also referred to herein as amedicament) comprising a therapeutically-effective amount of a compoundof Formula I, II, III or IV in association with at least onepharmaceutically-acceptable carrier, adjuvant or diluent.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the invention, compounds useful for treating Aurorakinase and related disorders, including cancer and inflammation, aredefined by Formula I:

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt orprodrug thereof, wherein

each of A¹ and A², independently, is N or CR², provided no more than oneof A¹ and A² is N;

each of A³, A⁴, A⁵ and A⁶, independently, is N or CR³, provided that nomore than two of A³, A⁴, A⁵ and A⁶ is N;

each of L¹ and L², independently, is —O—, —NR⁴—, —S—, —C(O)—, —S(O)—,—SO₂— or —CR⁴R⁴—, wherein each R⁴, independently, is H, halo, OH,C₁₋₆alkoxyl, NH—C₁₋₆alkyl, CN or C₁₋₆alkyl;

each of A⁷ and A⁸, independently, is N or CR⁵, provided at least one ofA⁷ and A⁸ is N;

D′ is a 5- or 6-membered ring of carbon atoms optionally including 1-3heteroatoms selected from O, N and S, and the ring optionallysubstituted independently with n number of substituents of R¹;

each R¹, independently, is halo, haloalkyl, haloalkoxyl, oxo, CN, OH,SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, —SR⁹, —OR⁹,—NR⁹R⁹, —C(O)R⁹, —COOR⁹, —OC(O)R⁹, —C(O)C(O)R⁹, —C(O)NR⁹R⁹, —NR⁹C(O)R⁹,—NR⁹C(O)NR⁹R⁹, —NR⁹(COOR⁹), —OC(O)NR⁹R⁹, —S(O)₂R⁹, —S(O)₂R⁹,—S(O)₂NR⁹R⁹, —NR⁹S(O)₂NR⁹R⁹, —NR⁹S(O)₂R⁹ or a fully saturated orpartially or fully unsaturated 3-8 membered monocyclic, 6-12 memberedbicyclic, or 7-14 membered tricyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein each ofthe C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of R⁹;

each R², independently, is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH,SH, NO₂, NH₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or —C(O)R⁹;

each R³, independently, is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH,SH, NO₂, NH₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or —C(O)R⁹;

R⁵ is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂, N12,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or —C(O)R⁹;

each of R⁶, R⁷ and R⁸, independently, is R⁹;

alternatively, either of R⁶ or R⁸, independently, taken together with R¹and the carbon atoms to which they are attached form a fully saturatedor partially or fully unsaturated 5- or 6-membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, and thering optionally substituted independently with 1-4 substituents of R⁹;

each R⁹, independently, is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH,SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, SR¹⁰, OR¹⁰,NR⁴R¹⁰, C(O)R¹⁰, COOR¹⁰, C(O)NR⁴R¹⁰, NR⁴C(O)R¹⁰, NR⁴C(O)NR⁴R¹⁰,NR⁴(COOR¹⁰), S(O)₂R¹⁰, S(O)₂NR⁴R¹⁰, NR⁴S(O)₂R¹⁰, NR⁴S(O)₂NR⁴R¹⁰ or afully saturated or partially or fully unsaturated 3-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of R¹⁰, halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH,oxo, C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl;

R¹⁰ is H, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a fullysaturated or partially or fully unsaturated 3-8 membered monocyclic or6-12 membered bicyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic or 1-6heteroatoms if bicyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH, oxo,C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl; and

n is 0, 1, 2, 3 or 4;

provided that (1) when D′ is a phenyl ring, A¹ is CH and A² is CR² inFormula I above, than R² is not CN; or (2) when A¹ is CH, A² is N and L′is —NR⁴—, then D′ is not

wherein one of X and Y is N and the other of X and Y is an optionallysubstituted carbon atom.

Accordingly, while the above embodiment includes quinoline D ringcompounds, the present invention does not encompass those compounds ofFormula I where when either of A¹ or A², independently, is CR², then R²is a cyano group. In addition, the present invention does not includethose compounds of Formula I wherein the D ring is pyrimidine ringhaving A¹ as CH and A² as N while the D′ ring is

wherein one of X and Y is N and the other of X and Y is an optionallysubstituted carbon atom.

In another embodiment, Formula I includes compounds wherein A¹ is N andA² is CR², in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein A¹ is CR²and A² is N, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein each of A¹and A² independently, is CR², in conjunction with any of the above orbelow embodiments.

In another embodiment, Formula I includes compounds wherein each of A¹and A² independently, is CR² wherein R² is either H or a halogen, inconjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein D′ is a5-membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N and S, and the ring optionally substitutedindependently with n number of substituents of R¹, in conjunction withany of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein D′ is a6-membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N and S, and the ring optionally substitutedindependently with n number of substituents of R¹, in conjunction withany of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein D′ is

wherein X¹ is O, S or NR¹, X² is CR¹ or N and R¹ and n are as defined inFormula I, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein D′ is

wherein X¹ is O, S or NR¹, X² is CR¹ or N and R¹ and n are as defined inFormula I, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein each of A³,A⁴, A⁵ and A⁶ is CR³, in conjunction with any of the above or belowembodiments.

In another embodiment, Formula I includes compounds wherein three of A³,A⁴, A⁵ and A⁶ is CH, and one of A³, A⁴, A⁵ and A⁶ is CR³, in conjunctionwith any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein each of A³,A⁴, A⁵ and A⁶ is CH, in conjunction with any of the above or belowembodiments.

In another embodiment, Formula I includes compounds wherein A³ is N andeach of A⁴, A⁵ and A⁶ is CR³, in conjunction with any of the above orbelow embodiments.

In another embodiment, Formula I includes compounds wherein A⁴ is N andeach of A³, A⁵ and A⁶ is CR³, in conjunction with any of the above orbelow embodiments.

In another embodiment, Formula I includes compounds wherein A⁵ is N andeach of A³, A⁴ and A⁶ is CR³, in conjunction with any of the above orbelow embodiments.

In another embodiment, Formula I includes compounds wherein A⁶ is N andeach of A³, A⁴ and A⁴ is CR³, in conjunction with any of the above orbelow embodiments.

In another embodiment, Formula I includes compounds wherein each of A³and A⁶ is N and each of A⁴ and A⁵ is CR³, in conjunction with any of theabove or below embodiments.

In another embodiment, Formula I includes compounds wherein each of A⁴and A⁵ is N and each of A³ and A⁶ is CR³, in conjunction with any of theabove or below embodiments.

In another embodiment, Formula I includes compounds wherein each of A³and A⁴ is N and each of A⁵ and A⁶ is CR³, in conjunction with any of theabove or below embodiments.

In another embodiment, Formula I includes compounds wherein A⁷ is N andA⁸ is CR⁵, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein A³ is N andA⁷ is CR⁵, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein each of A⁷and A⁸ is N, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L¹ is —O—,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L¹ is —NR⁴—,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L¹ is —NH—,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L¹ is —S—,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L¹ is—C(O)—, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L¹ is—S(O)—, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L¹ is —SO₂—,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L¹ is—CR⁴R⁴—, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L¹ is —O—,—NR⁴— or —S—, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L¹ is —O— or—S—, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L² is —O—,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L² is —NR¹—,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L² is —NH—,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L² is —S—,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L² is—C(O)—, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L² is—S(O)—, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L² is —SO₂—,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L² is—CR⁴R⁴—, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R¹ is halo,haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SR⁹, —OR⁹, —NR⁹R⁹ or —C(O)R⁹, in conjunction withany of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R¹ is COOR⁹,—OC(O)R⁹, —C(O)C(O)R⁹, —C(O)NR⁹R⁹, —NR⁹C(O)R⁹, —NR⁹C(O)NR⁹R⁹,—NR⁹(COOR⁹), —OC(O)NR⁹R⁹, —S(O)₂R⁹, —S(O)₂R⁹, —S(O)₂NR⁹R⁹,—NR⁹S(O)₂NR⁹R⁹ or —NR⁹S(O)₂R⁹, in conjunction with any of the above orbelow embodiments.

In another embodiment, Formula I includes compounds wherein R¹ is afully saturated or partially or fully unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, Formula I includes compounds wherein each R²,independently, is H, halo, haloalkyl, haloalkoxyl, CN, OH, SH, NO₂, NH₂,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or —C(O)R⁹, in conjunction with any ofthe above or below embodiments.

In another embodiment, Formula I includes compounds wherein each R²,independently, is H, halo, CF₃, CN, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, methylamine, dimethylamine,ethylamine, diethylamine, propylamine or isopropylamine, in conjunctionwith any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein each R²,independently, is R² is H, halo, haloalkyl, haloalkoxyl, OH, SH, NO₂,NH₂, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkylamino-,C₁₋₆-alkoxyl, C₁₋₆-thioalkoxyl or —C(O)R⁹, in conjunction with any ofthe above or below embodiments.

In another embodiment, Formula I includes compounds wherein each R³,independently, is H, halo, haloalkyl, haloalkoxyl, CN, OH, SH, NO₂, NH₂,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or —C(O)R⁹, in conjunction with any ofthe above or below embodiments.

In another embodiment, Formula I includes compounds wherein each R³,independently, is R² is H, halo, haloalkyl, haloalkoxyl, OH, SH, NO₂,NH₂, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₄-alkynyl, C₁₋₆-alkylamino-,C₁₋₆-alkoxyl, C₁₋₆-thioalkoxyl or —C(O)R⁹, in conjunction with any ofthe above or below embodiments.

In another embodiment, Formula I includes compounds wherein each R³,independently, is H, halo, CF₃, CN, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, methylamine, dimethylamine,ethylamine, diethylamine, propylamine or isopropylamine, in conjunctionwith any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein each R⁴,independently, is H, halo, OH, C₁₋₆alkoxyl, NH—C₁₋₆alkyl, CN orC₁₋₆alkyl, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein each R⁴,independently, is H, CN or C₁₋₆alkyl, in conjunction with any of theabove or below embodiments.

In another embodiment, Formula I includes compounds wherein each R⁴,independently, is H or C₁₋₆alkyl, in conjunction with any of the aboveor below embodiments.

In another embodiment, Formula I includes compounds wherein R⁵ is H,halo, haloalkyl, haloalkoxyl, CN, OH, SH, NO₂, NH₂, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor —C(O)R⁹, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R⁵ is H,halo, CF₃, CN, NO₂, NH₂, OH, methyl, methoxyl, ethyl, ethoxyl, propyl,propoxyl, isopropyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine or isopropylamine, in conjunction with any ofthe above or below embodiments.

In another embodiment, Formula I includes compounds wherein R⁶ is afully saturated or partially or fully unsaturated 3-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of R¹⁰, halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH,oxo, C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl, in conjunction with any of theabove or below embodiments.

In another embodiment, Formula I includes compounds wherein R⁶ isphenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyazinyl,triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl,phthalazinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl,thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl,benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, benzodioxolyl,hexahydropyrrolo[1,2-a]pyrazinyl, cyclopropyl, cyclobutyl, azetidinyl,cyclopentyl, cyclohexyl, cycloheptyl or pyranyl, each of which isoptionally substituted independently with 1-5 substituents of R¹⁰, halo,haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH, oxo, C₁₋₆alkyl, C₁₋₆alkoxyl,C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, benzyl orphenyl, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein each of R⁷and R⁸ independently, is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH,SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, SR¹⁰, OR¹⁰,NR⁴R¹⁰, C(O)R¹⁰, in conjunction with any of the above or belowembodiments.

In another embodiment, Formula I includes compounds wherein either of R⁷or R⁸, independently, is a fully saturated or partially or fullyunsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyland ring of said ring system is optionally substituted independentlywith 1-5 substituents of R¹⁰, halo, haloalkyl, haloalkoxyl, CN, NO₂,NH₂, OH, oxo, C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl, in conjunction with any of theabove or below embodiments.

In another embodiment, Formula I includes compounds wherein R⁸ takentogether with R⁷ and the carbon atoms to which they are attached form afully saturated or partially or fully unsaturated 5- or 6-membered ringof carbon atoms optionally including 1-3 heteroatoms selected from O, N,or S, and the ring optionally substituted independently with 1-4substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, Formula I includes compounds wherein R⁸ takentogether with R⁷ and the carbon atoms to which they are attached form aring selected from phenyl, cyclohexyl, thienyl, furyl, pyridyl,pyrimidyl and cyclopenyl, the ring optionally substituted independentlywith 14 substituents of R⁹, in conjunction with any of the above orbelow embodiments.

In another embodiment, Formula I includes compounds wherein R⁸ takentogether with R⁷ and the carbon atoms to which they are attached form aring selected from phenyl, pyridyl and pyrimidyl, the ring optionallysubstituted independently with 1-4 substituents of R⁹, in conjunctionwith any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R⁸ takentogether with R⁷ and the carbon atoms to which they are attached form aphenyl ring, optionally substituted independently with 1-4 substituentsof R⁹, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R⁶ is afully saturated or partially or fully unsaturated 3-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of R¹⁰, halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH,oxo, C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl; and

R⁷ and R⁸, taken together with the carbon atoms to which they areattached form a fully saturated or partially or fully unsaturated 5- or6-membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and the ring optionally substitutedindependently with 1-4 substituents of R⁹, in conjunction with any ofthe above or below embodiments.

In another embodiment, Formula I includes compounds wherein R⁶ is afully saturated or partially or fully unsaturated 3-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of R¹⁰, halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH,oxo, C₁₋₁₀alkyl, C₁₋₁₀alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl; and

R⁷ and R⁸, taken together with the carbon atoms to which they areattached form a phenyl ring, optionally including 1-3 heteroatomsselected from O, N, or S, and the ring optionally substitutedindependently with 1-4 substituents of R⁹, in conjunction with any ofthe above or below embodiments.

In another embodiment, Formula I includes compounds wherein

each of A¹ and A², independently, is CR²;

L¹ is —O—, —S— or —NR⁴—;

L² is —NR⁴—; and

R⁶ is phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyazinyl,triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl,phthalazinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl,thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl,benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, benzodioxolyl,hexahydropyrrolo[1,2-a]pyrazinyl, cyclopropyl, cyclobutyl, azetidinyl,cyclopentyl, cyclohexyl, cycloheptyl or pyranyl, each of which isoptionally substituted independently with 1-5 substituents of R¹⁰, halo,haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH, oxo, C₁₋₆alkyl, C₁₋₆alkoxyl,C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, benzyl orphenyl, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of the present invention includecompounds of Formula II:

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt orprodrug thereof, wherein

A² is N or CR²;

each of A³, A⁴, A⁵ and A⁶, independently, is N or CR³, provided that nomore than two of A³, A⁴, A⁵ and A⁶ is N;

L¹ is —O—, —S—, or —NR⁴—;

D′ is a 5- or 6-membered ring of carbon atoms optionally including 1-3heteroatoms selected from O, N and S, and the ring optionallysubstituted independently with n number of substituents of R¹;

each R¹, independently, is halo, haloalkyl, haloalkoxyl, oxo, CN, OH,SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, —SR⁹, —OR⁹,—NR⁹R⁹, —C(O)R⁹, —COOR⁹, —OC(O)R⁹, —C(O)C(O)R⁹, —C(O)NR⁹R⁹, —NR⁹C(O)R⁹,—NR⁹C(O)NR⁹R⁹, —NR⁹(COOR⁹), —OC(O)NR⁹R⁹, —S(O)₂R⁹, —S(O)₂R⁹,—S(O)₂NR⁹R⁹, —NR⁹S(O)₂NR⁹R⁹, —NR⁹S(O)₂R⁹ or a fully saturated orpartially or fully unsaturated 3-8 membered monocyclic, 6-12 memberedbicyclic, or 7-14 membered tricyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein each ofthe C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of R⁹;

R² is H, halo, haloalkyl, haloalkoxyl, oxo, OH, SH, NO₂, NH₂,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or —C(O)R⁹;

each R³, independently, is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH,SH, NO₂, NH₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or —C(O)R⁹;

each R⁴, independently, is H or C₁₋₆alkyl;

R⁶ is a fully saturated or partially or fully unsaturated 3-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of R¹⁰, halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH,oxo, C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl;

each of R⁷ and R⁸, independently, is R⁹;

alternatively, R⁷ and R⁸ independently, taken together with the carbonatoms to which they are attached form a fully saturated or partially orfully unsaturated 5- or 6-membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-4 substituents of R⁹;

each R⁹, independently, is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH,SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, SR¹⁰, OR¹⁰,NR⁴R¹⁰, C(O)R¹⁰, COOR¹⁰, C(O)NR⁴R¹⁰, NR⁴C(O)R¹⁰, NR⁴C(O)NR⁴R¹⁰,NR⁴(COOR¹⁰), S(O)₂R¹⁰, S(O)₂NR⁴R¹⁰, NR⁴S(O)₂R¹⁰, NR⁴S(O)₂NR⁴R¹⁰ or afully saturated or partially or fully unsaturated 3-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of R¹⁰, halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH,oxo, C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl;

R¹⁰ is H, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a fullysaturated or partially or fully unsaturated 3-8 membered monocyclic or6-12 membered bicyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic or 1-6heteroatoms if bicyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-substituentsof halo, haloalkyl, haloalkoxyl, CN, NO₂, N142, OH, oxo, C₁₋₆alkyl,C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,benzyl or phenyl; and

n is 0, 1, 2, 3 or 4;

provided that (1) when A² is N and L¹ is —NR⁴—, then D′ is not

wherein one of X and Y is N and the other of X and Y is an optionallysubstituted carbon atom.

In another embodiment, Formula II includes compounds wherein D′ is

wherein X is O, S or NR¹ and R¹ and n are as defined in the immediatelypreceeding embodiment; and

L¹ is —O— or —S—, in conjunction with any of the above or belowembodiments.

In another embodiment, Formula II includes compounds wherein R⁶ is afully saturated or partially or fully unsaturated 3-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of R¹⁰, halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH,oxo, C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl; and R⁷ and R⁸, taken togetherwith the carbon atoms to which they are attached form a fully saturatedor partially or fully unsaturated 5- or 6-membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, and thering optionally substituted independently with 1-4 substituents of R⁹,in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of the present invention includecompounds of Formula II-A:

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt orprodrug thereof, wherein

A² is N or CR²;

each of A³ and A⁶, independently, is N or CR³, provided that no morethan one of A³ and A⁶ is N;

L¹ is —O—, —S—, or —NR⁴—;

D′ is a 5- or 6-membered ring of carbon atoms optionally including 1-3heteroatoms selected from O, N and S, and the ring optionallysubstituted independently with n number of substituents of R¹;

each R¹, independently, is halo, haloalkyl, haloalkoxyl, oxo, CN, OH,SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, —SR⁹, —OR⁹,—NR⁹R⁹, —C(O)R⁹, —COOR⁹, —OC(O)R⁹, —C(O)C(O)R⁹, —C(O)NR⁹R⁹, —NR⁹C(O)R⁹,—NR⁹C(O)NR⁹R⁹, —NR⁹(COOR⁹), —OC(O)NR⁹R⁹, —S(O)₂R⁹, —S(O)₂R⁹,—S(O)₂NR⁹R⁹, —NR⁹S(O)₂NR⁹R⁹, —NR⁹S(O)₂R⁹ or a fully saturated orpartially or fully unsaturated 3-8 membered monocyclic, 6-12 memberedbicyclic, or 7-14 membered tricyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein each ofthe C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of R⁹;

R² is H, halo, haloalkyl, haloalkoxyl, OH, SH, NO₂, NH₂, C₁₋₆-alkyl,C₂₋₄-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkylamino-, C₁₋₆-alkoxyl,C₁₋₆-thioalkoxyl or —C(O)R⁹;

each R³, independently, is H, halo, haloalkyl, haloalkoxyl, OH, SH, NO₂,NH₂, C₁₋₆alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkylamino-,C₁₋₆-alkoxyl, C₁₋₆-thioalkoxyl or —C(O)R⁹;

R⁴ is H or C₁₋₆alkyl;

R⁶ is R⁹;

each R⁹, independently, is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH,SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, SR¹⁰, OR¹⁰,NR⁴R¹⁰, C(O)R¹⁰, COOR¹⁰, C(O)NR⁴R¹⁰, NR⁴C(O)R¹⁰, NR⁴C(O)NR⁴R¹⁰,NR⁴(COOR¹⁰), S(O)₂R¹⁰, S(O)₂NR⁴R¹⁰, NR⁴S(O)₂R¹⁰, NR⁴S(O)₂NR⁴R¹⁰ or afully saturated or partially or fully unsaturated 3-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of R¹⁰, halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH,oxo, C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl;

R¹⁰ is H, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a fullysaturated or partially or fully unsaturated 3-8 membered monocyclic or6-12 membered bicyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic or 1-6heteroatoms if bicyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH, oxo,C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl;

n is 0, 1, 2, 3 or 4; and

o is 0, 1, 2, 3 or 4.

In another embodiment, the compounds of the present invention includecompounds of Formula III:

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt orprodrug thereof, wherein

one of A¹ and A² is N and the other of one of A¹ and A² is CR²;

each of A³, A⁴, A⁵ and A⁶, independently, is N or CR³, provided that nomore than two of A³, A⁴, A⁵ and A⁶ is N;

each of L¹ and L², independently, is —O—, —NR⁴—, —S—, —C(O)—, —S(O)—,—SO₂— or —CR⁴R⁴—, wherein each R⁴, independently, is H or C₁₋₆alkyl;

each R¹, independently, is H, halo, haloalkyl, haloalkoxyl, CN, OH, SH,NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, —SR⁹, —OR⁹,—NR⁹R⁹, —C(O)R⁹, —COOR⁹, —OC(O)R⁹, —C(O)C(O)R⁹, —C(O)NR⁹R⁹, —NR⁹C(O)R⁹,—NR⁹C(O)NR⁹R⁹, —NR⁹(COOR⁹), —OC(O)NR⁹R⁹, —S(O)₂R⁹, —S(O)₂R⁹,—S(O)₂NR⁹R⁹, —NR⁹S(O)₂NR⁹R⁹, —NR⁹S(O)₂R⁹ or a fully saturated orpartially or fully unsaturated 3-8 membered monocyclic, 6-12 memberedbicyclic, or 7-14 membered tricyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein each ofthe C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of R⁹;

R² is H, halo, haloalkyl, haloalkoxyl, oxo, OH, SH, NO₂, NH₂,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or —C(O)R⁹;

each R³, independently, is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH,SH, NO₂, NH₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or —C(O)R⁹;

R⁶ is R⁹;

each R⁹, independently, is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH,SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, SR¹⁰, OR¹⁰,NR⁴R¹⁰, C(O)R¹⁰, COOR¹⁰, C(O)NR⁴R¹⁰, NR⁴C(O)R¹⁰, NR⁴C(O)NR⁴R¹⁰,NR⁴(COOR¹⁰), S(O)₂R¹⁰, S(O)₂NR⁴R¹⁰, NR⁴S(O)₂R¹⁰, NR⁴S(O)₂NR⁴R¹⁰ or afully saturated or partially or fully unsaturated 3-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of R¹⁰, halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH,oxo, C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl;

R¹⁰ is H, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a fullysaturated or partially or fully unsaturated 3-8 membered monocyclic or6-12 membered bicyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic or 1-6heteroatoms if bicyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH, oxo,C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl; and

n is 0, 1, 2, 3 or 4.

In another embodiment, Formula III compounds include compounds wherein

A¹ is CR² and A² is N;

each of A³, A⁴, A⁵ and A⁶ independently, is CR³;

L¹ is —O—, —NR⁴— or —S—;

L² is —NR⁴—;

each R¹, independently, is H, halo, CF₃, C₂F₅, haloalkoxyl, CN, OH, SH,NO₂, NH₂, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl,cyclopentyl, hexyl, cyclohexyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, —C(O)R⁹, —COOR⁹, —C(O)NHR⁹, —NHC(O)R⁹, —NHC(O)NHR⁹,—NH(COOR⁹), —S(O)₂R⁹, —S(O)₂R⁹, —S(O)₂NHR⁹, —NHS(O)₂NHR⁹, —NHS(O)₂R⁹ ora ring selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl,pyazinyl, triazinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl,pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl,thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl,isothiazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl,cycloheptyl or pyranyl, said ring optionally substituted independentlywith 1-5 substituents of R⁹;

R² is H, halo, CF₃, CN, NO₂, NH₂, OH, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine or isopropylamine;

each R³, independently, is H, halo, CF₃, CN, NO₂, NH₂, OH, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, methylamine,dimethylamine, ethylamine, diethylamine, propylamine or isopropylamine;

each R⁴, independently, is H or C₁₋₆alkyl; and

R⁶ is phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyazinyl,triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl,phthalazinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl,thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl,benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, benzodioxolyl,hexahydropyrrolo[1,2-a]pyrazinyl, cyclopropyl, cyclobutyl, azetidinyl,cyclopentyl, cyclohexyl, cycloheptyl or pyranyl, each of which isoptionally substituted independently with 1-5 substituents of R¹⁰, halo,haloalkyl, haloalkoxyl, CN, NO₂, N12, OH, oxo, C₁₋₆alkyl, C₁₋₆alkoxyl,C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, benzyl orphenyl, in conjunction with any of the above or below embodiments.

In another embodiment, Formula III compounds include compounds wherein

A¹ is CR² and A² is N;

one of A³, A⁴, A⁵ and A⁶ is N and others of A³, A⁴, A⁵ and A⁶ are eachCR³;

L¹ is —O—, —NR⁴— or —S—;

L² is —NR⁴—;

each R¹, independently, is H, halo, CF₃, C₂F₅, haloalkoxyl, CN, OH, SH,NO₂, NH₂, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl,cyclopentyl, hexyl, cyclohexyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, —C(O)R⁹, —COOR⁹, —C(O)NHR⁹, —NHC(O)R⁹, —NHC(O)NHR⁹,—NH(COOR⁹), —S(O)₂R⁹, —S(O)₂R⁹, —S(O)₂NHR⁹, —NHS(O)₂NHR⁹, —NHS(O)₂R⁹ ora ring selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl,pyazinyl, triazinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl,pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl,thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl,isothiazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl,cycloheptyl or pyranyl, said ring optionally substituted independentlywith 1-5 substituents of R⁹;

R² is H, halo, CF₃, CN, NO₂, NH₂, OH, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine or isopropylaamine;

each R³, independently, is H, halo, CF₃, CN, NO₂, NH₂, OH, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, methylamine,dimethylamine, ethylamine, diethylamine, propylamine or isopropylamine;

each R⁴, independently, is H or C₁₋₆alkyl; and

R⁶ is phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyazinyl,triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl,phthalazinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl,thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl,benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, benzodioxolyl,hexahydropyrrolo[1,2-a]pyrazinyl, cyclopropyl, cyclobutyl, azetidinyl,cyclopentyl, cyclohexyl, cycloheptyl or pyranyl, each of which isoptionally substituted independently with 1-5 substituents of R¹⁰, halo,haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH, oxo, C₁₋₆alkyl, C₁₋₆alkoxyl,C₃₋₄cycloalkyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, benzyl orphenyl.

In another embodiment, the compounds of the present invention includecompounds of Formula III-A:

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt orprodrug thereof, wherein

A² is CR² or N;

A³ is N or CR³;

L¹ is —O—, —NR⁴—, —S—, —C(O)—, —S(O)—, —SO₂— or —CR⁴R⁴—, wherein eachR⁴, independently, is H or C₁₋₆alkyl;

each R¹, independently, is H, halo, haloalkyl, haloalkoxyl, CN, OH, SH,NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, —SR⁹, —OR⁹,—NR⁹R⁹, —C(O)R⁹, —COOR⁹, —OC(O)R⁹, —C(O)C(O)R⁹, —C(O)NR⁹R⁹, —NR⁹C(O)R⁹,—NR⁹C(O)NR⁹R⁹, —NR⁹(COOR⁹), —OC(O)NR⁹R⁹, —S(O)₂R⁹, —S(O)₂R⁹,—S(O)₂NR⁹R⁹, —NR⁹S(O)₂NR⁹R⁹, —NR⁹S(O)₂R⁹ or a fully saturated orpartially or fully unsaturated 3-8 membered monocyclic, 6-12 memberedbicyclic, or 7-14 membered tricyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein each ofthe C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of R⁹;

each R², independently, is H, halo, haloalkyl, haloalkoxyl, oxo, OH, SH,NO₂, NH₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or —C(O)R⁹;

each R³, independently, is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH,SH, NO₂, NH₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or —C(O)R⁹;

R⁶ is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂,acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, SR¹⁰, OR¹⁰, NR⁴R¹⁰, C(O)R¹⁰, COOR¹⁰,C(O)NR⁴R¹⁰, NR⁴C(O)R¹⁰, NR⁴C(O)NR⁴R¹⁰, NR⁴ (COOR¹⁰), S(O)₂R¹⁰,S(O)₂NR⁴R¹⁰, NR⁴S(O)₂R¹⁰, NR⁴S(O)₂NR⁴R¹⁰ or a fully saturated orpartially or fully unsaturated 3-8 membered monocyclic or 6-12 memberedbicyclic ring system, said ring system formed of carbon atoms optionallyincluding 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic,said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of R⁹;

each R⁹, independently, is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH,SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, SR¹⁰, OR¹⁰,NR⁴R¹⁰, C(O)R¹⁰, COOR¹⁰, C(O)NR⁴R¹⁰, NR⁴C(O)R¹⁰, NR⁴C(O)NR⁴R¹⁰,NR⁴(COOR¹⁰), S(O)₂R¹⁰, S(O)₂NR⁴R¹⁰, NR⁴S(O)₂R¹⁰, NR⁴S(O)₂NR⁴R¹⁰ or afully saturated or partially or fully unsaturated 3-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of R¹⁰, halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH,oxo, C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl;

R¹⁰ is H, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a fullysaturated or partially or fully unsaturated 3-8 membered monocyclic or6-12 membered bicyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic or 1-6heteroatoms if bicyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH, oxo,C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl; and

n is 0, 1, 2, 3 or 4.

In yet another embodiment, the invention provides compounds generallydefined by Formula IV:

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt orprodrug thereof, wherein

each of A⁴ and A⁵, independently, is N or CR³;

L¹ is —O—, —NR⁴—, —S—, —C(O)—, —S(O)—, —SO₂— or —CR⁴R⁴—, wherein eachR⁴, independently, is H, halo, OH, C₁₋₆alkoxyl, NH—C₁₋₆alkyl, CN orC₁₋₆alkyl;

D is a fully saturated or partially or fully unsaturated 8-12 memberedbicyclic ring system, said ring system formed of carbon atoms optionallyincluding 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic,said heteroatoms selected from O, N, or S, and said ring optionallysubstituted independently with n number of substituents of R¹;

each R¹, independently, is halo, haloalkyl, haloalkoxyl, oxo, CN, OH,SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, —SR⁹, —OR⁹—NR⁹R⁹, —C(O)R⁹, —COOR⁹, —OC(O)R⁹, —C(O)C(O)R⁹, —C(O)NR⁹R⁹, —NR⁹C(O)R⁹,—NR⁹C(O)NR⁹R⁹, —NR⁹(COOR⁹), —OC(O)NR⁹R⁹, —S(O)₂R⁹, —S(O)₂R⁹,—S(O)₂NR⁹R⁹, —NR⁹S(O)₂NR⁹R⁹, —NR⁹S(O)₂R⁹ or a fully saturated orpartially or fully unsaturated 3-8 membered monocyclic, 6-12 memberedbicyclic, or 7-14 membered tricyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein each ofthe C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of R⁹;

each R³, independently, is H, halo, haloalkyl, haloalkoxyl, CN, OH, SH,NO₂, NH₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor —C(O)C₁₋₁₀-alkyl;

R⁵ is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or —C(O)R⁹;

R⁶ is R⁹;

R⁹ is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂,acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, SR¹⁰, OR¹⁰, NR⁴R¹⁰, C(O)R¹⁰, COOR¹⁰,C(O)NR⁴R¹⁰, NR⁴C(O)R¹⁰, NR⁴C(O)NR⁴R¹⁰, NR⁴(COOR¹⁰), S(O)₂R¹⁰,S(O)₂NR⁴R¹⁰, NR⁴S(O)₂R¹⁰, NR⁴S(O)₂NR⁴R¹⁰ or a fully saturated orpartially or fully unsaturated 3-8 membered monocyclic or 6-12 memberedbicyclic ring system, said ring system formed of carbon atoms optionallyincluding 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic,said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of R¹⁰, halo,haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH, oxo, C₁₋₆alkyl, C₁₋₆alkoxyl,C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, benzyl orphenyl;

R¹⁰ is H, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a fullysaturated or partially or fully unsaturated 3-8 membered monocyclic or6-12 membered bicyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic or 1-6heteroatoms if bicyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH, oxo,C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl; and

n is 0, 1, 2, 3 or 4; and

o is 0, 1, 2, 3 or 4.

In another embodiment, Formula IV compound include compounds whereineach of A⁴ and A⁵, independently, is CR³, in conjunction with any of theabove or below embodiments.

In another embodiment, Formula IV compound include compounds wherein R⁶is a fully saturated or partially or fully unsaturated 3-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of R¹⁰, halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH,oxo, C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl, in conjunction with any of theabove or below embodiments.

In another embodiment, Formula IV compound include compounds wherein R⁶is phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyazinyl,triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl,phthalazinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl,thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl,benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, benzodioxolyl,hexahydropyrrolo[1,2-a]pyrazinyl, cyclopropyl, cyclobutyl, azetidinyl,cyclopentyl, cyclohexyl, cycloheptyl or pyranyl, each of which isoptionally substituted independently with 1-5 substituents of R¹⁰, halo,haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH, oxo, C₁₋₆alkyl, C₁₋₆alkoxyl,C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, benzyl orphenyl, in conjunction with any of the above or below embodiments.

In another embodiment, Formula IV compound include compounds whereinring D is a 8-, 9- or 10-membered fused bicyclic ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N and S, and thering optionally substituted independently with n number of substituentsof R¹, in conjunction with any of the above or below embodiments.

The many different embodiments for the various elements, chemicalmoieties or R or L groups described and defined hereinabove with respectto compounds of Formula I also apply, and are included herein, tocompounds of Formula II, II-A, III, III-A and IV where appropriate, asappreciated by those of ordinary skill in the art.

In yet another embodiment, Formulas I, II, II-A, III, III-A and IVinclude the exemplary compounds and derivatives, prodrugs, solvates,tautomers and pharmaceutically acceptable salt forms thereof,intermediates related thereto, examples of which are described in theExamples herein. For example, and in another embodiment, the inventionprovides the following compounds, and pharmaceutically acceptable saltforms thereof, selected from:′N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-4-phenyl-1-phthalazinamine;

-   ′N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-4-(4-methyl-1,3-thiazol-2-yl)-1-phthalazinamine;-   ′4-ethyl-N-(6-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)-3-pyridinyl)-6-phenyl-3-pyridazinamine;-   ′4-((4-((4-(4-methyl-1,3-thiazol-2-yl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;-   ′N-(3-fluoro-4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-4-phenyl-1-phthalazinamine;-   ′N-(4-((7-(methyloxy)-1,6-naphthyridin-4-yl)oxy)phenyl)-4-phenyl-1-phthalazinamine;-   ′N-(4-((6,7-bis(methyloxy)-4-quinazolinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine;-   ′N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-4-(4-methyl-2-pyridinyl)-1-phthalazinamine;-   ′N-(7-(methyloxy)-1,6-naphthyridin-4-yl)-N′-(4-phenyl-1-phthalazinyl)-1,4-benzenediamine;-   ′N-3-(methyloxy)-8-((4-((4-(4-methylphenyl)-1-phthalazinyl)methyl)phenyl)oxy)-1,5-naphthyridine;-   ′N-(6-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)-3-pyridinyl)-4-(6-methyl-2-pyridinyl)-1-phthalazinamine;    ′4-(5-chloro-2-thienyl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine;-   ′4-((4-((4-(4-(methyloxy)phenyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;-   ′4-(1-methyl-1H-indol-2-yl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine;-   ′N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-4-(4-(trifluoromethyl)phenyl)-1-phthalazinamine;-   ′4-((4-((4-(4-(trifluoromethyl)phenyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;    and    ′4-(4-chlorophenyl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine.

In another embodiment, the invention provides the following compounds,and pharmaceutically acceptable salt forms thereof, selected from

-   ′4-(1,3-benzodioxol-5-yl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine;-   ′4-(2,3-dihydro-1-benzofuran-5-yl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine;-   ′4-(3-chloro-4-(trifluoromethyl)phenyl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine;-   ′4-(6-fluoro-3-pyridinyl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine;-   ′4-(3-chloro-4-fluorophenyl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine;-   ′4-(2-methyl-1,3-benzothiazol-5-yl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine;-   ′4-(3,4-dichlorophenyl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine;-   ′N-(4-((2-(1-methyl-1H-imidazol-5-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-4-phenyl-1-phthalazinamine;    ′4-(1-methyl-1H-indol-5-yl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine;-   ′4-ethyl-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-6-(5-methyl-2-thienyl)-3-pyridazinamine;    and-   4-(1,3-benzodioxol-5-yl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine.

In another embodiment, the invention provides the following compounds,and pharmaceutically acceptable salt forms thereof, selected fromN-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-4-(5-pyrimidinyl)-1-phthalazinamine;

-   ′N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-4-phenylthieno[2,3-d]pyridazin-7-amine;-   ′4-(4-fluorophenyl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine;-   ′4-(4-chlorophenyl)-N-(6-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)-3-pyridinyl)-1-phthalazinamine;-   ′4-(5-chloro-2-pyridinyl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine;-   ′4-(6-chloro-3-pyridinyl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine;-   ′4-(4-fluoro-3-methylphenyl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine;-   ′4-((4-((4-(4-chlorophenyl)-1-phthalazinyl)amino)phenyl)thio)-7-quinolinecarbonitrile;-   ′4-(4-chlorophenyl)-N-(4-(thieno[3,2-b]pyridin-7-yloxy)phenyl)-1-phthalazinamine;-   ′8-((4-((4-(4-chlorophenyl)-1-phthalazinyl)amino)phenyl)oxy)-1,5-naphthyridine-3-carbonitrile;-   N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)thio)phenyl)-4-phenyl-1-phthalazinamine;-   N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine;-   4-ethyl-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-6-phenylpyridazin-3-amine;-   6-(4-chlorophenyl)-4-ethyl-N-(6-(7-methoxy-1,5-naphthyridin-4-yloxy)pyridin-3-yl)pyridazin-3-amine;-   6-(4-chlorophenyl)-4-ethyl-N-(6-(7-methoxy-1,5-naphthyridin-4-yloxy)pyridin-3-yl)pyridazin-3-amine;-   ′N-(4-((6-(methyloxy)-4-quinolinyl)thio)phenyl)-4-phenyl-1-phthalazinamine;-   ′N-(4-((2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridin-7-yl)thio)phenyl)-4-phenyl-1-phthalazinamine;    and

′4-(5-chloro-2-pyridinyl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)thio)phenyl)-1-phthalazinamine.

DEFINITIONS

The following definitions should further assist in understanding thescope of the invention described herein.

The terms “cancer” and “cancerous” when used herein refer to or describethe physiological condition in mammals that is typically characterizedby unregulated cell growth. Examples of cancer include, withoutlimitation, carcinoma, lymphoma, sarcoma, blastoma and leukemia. Moreparticular examples of such cancers include squamous cell carcinoma,lung cancer, pancreatic cancer, cervical cancer, bladder cancer,hepatoma, breast cancer, colon carcinoma, and head and neck cancer.While the term “cancer” as used herein is not limited to any onespecific form of the disease, it is believed that the methods of theinvention will be particularly effective for cancers which are found tobe accompanied by unregulated levels of Aurora kinase(s) in the mammal.

The terms “treat”, “treating” and “treatment” as used herein refer totherapy, including without limitation, curative therapy, prophylactictherapy, and preventative therapy. Prophylactic treatment generallyconstitutes either preventing the onset of disorders altogether ordelaying the onset of a pre-clinically evident stage of disorders inindividuals.

The term “mammal” as used herein refers to any mammal classified as amammal, including humans, cows, horses, dogs and cats. In one embodimentof the invention, the mammal is a human.

A “pharmaceutically-acceptable derivative” denotes any salt (alsoreferred to as “pharmaceutically-acceptable salt”), any prodrug such asa phospshate or an ester of a compound of this invention, or any othercompound which upon administration to a patient is capable of providing(directly or indirectly) a compound of this invention, or a metaboliteor residue thereof, characterized by the ability to inhibit Aurorakinase.

The phrase “therapeutically-effective” is intended to quantify theamount of each agent, which will achieve the goal of improvement indisorder severity and the frequency of incidence over treatment of eachagent by itself, while avoiding adverse side effects typicallyassociated with alternative therapies.

The terms “ring” and “ring system” refer to a one or more rings,typically fused together where more than one ring, comprising thedelineated number of atoms, said atoms being carbon or, where indicated,a heteroatom such as nitrogen, oxygen or sulfur. The ring itself, aswell as any substitutents thereon, may be attached at any atom thatallows a stable compound to be formed. The term “nonaromatic” ring orring system refers to the fact that at least one, but not necessarilyall, rings in a bicyclic or tricyclic ring system is not fullyunsaturated.

“Leaving groups” generally refer to groups that are displaceable by anucleophile. Such leaving groups are known in the art. Examples ofleaving groups include, but are not limited to, halides (e.g., 1, Br, F,Cl), sulfonates (e.g., mesylate, tosylate), sulfides (e.g., SCH₃),N-hydroxsuccinimide, N-hydroxybenzotriazole, and the like. Nucleophilesare species that are capable of attacking a molecule at the point ofattachment of the leaving group causing displacement of the leavinggroup. Nucleophiles are known in the art. Examples of nucleophilicgroups include, but are not limited to, amines, thiols, alcohols,Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions)and the like.

Where the term “alkyl” is used, either alone or within other terms suchas “haloalkyl” and “alkylamino”, it embraces linear or branched radicalspreferably having alpha to beta number of carbon atoms. For example aC₁-C₁₀alkyl is an alkyl comprising 1 to 10 carbon atoms. Examples ofsuch radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like. Itis contemplated herein that alkyl radicals may be optionally substitutedwith various substituents, where indicated.

The term “alkenyl”, alone or in combination, embraces linear or branchedradicals having at least one carbon-carbon double bond and having two ormore carbon atoms. Examples of alkenyl radicals include, withoutlimitation, ethenyl, propenyl, allyl, propenyl, butenyl and4-methylbutenyl. The term “alkenyl” embrace radicals having “cis” and“trans” orientations, or alternatively, “E” and “Z” orientations, asappreciated by those of ordinary skill in the art. It is contemplatedherein that alkenyl radicals may be optionally substituted with varioussubstituents, where indicated.

The term “alkynyl”, alone or in combination, denotes linear or branchedradicals having at least one carbon-carbon triple bond and having two ormore carbon atoms. Examples of alkynyl radicals include, withoutlimitation, ethynyl, propynyl (propargyl), butynyl, and the like. It iscontemplated herein that alkynyl radicals may be optionally substitutedwith various substituents, where indicated.

The term “halo”, alone or in combination, means halogens such asfluorine, chlorine, bromine or iodine atoms.

The term “haloalkyl”, alone or in combination, embraces radicals whereinany one or more of the alkyl carbon atoms is substituted with halo asdefined above. For example, this term includes monohaloalkyl,dihaloalkyl and polyhaloalkyl radicals such as a perhaloalkyl. Amonohaloalkyl radical, for example, may have either an iodo, bromo,chloro or fluoro atom within the radical. Dihalo and polyhaloalkylradicals may have two or more of the same halo atoms or a combination ofdifferent halo radicals. Examples of haloalkyl radicals includefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. “Perfluoroalkyl”, asused herein, refers to alkyl radicals having all hydrogen atoms replacedwith fluoro atoms. Examples include trifluoromethyl andpentafluoroethyl.

The term “alkoxy”, alone or in combination, embraces linear or branchedoxy-containing radicals each having alkyl portions of alpha to betanumber of carbon atoms. For example, a C₁₋₁₀ alkoxy radical indicates analkoxide having one to ten carbon atoms, arranged in a linear orbranched fashion, attached to an oxygen atom. Examples of such radicalsinclude methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Alkoxyradicals may be further substituted with one or more halo atoms, such asfluoro, chloro or bromo, to provide “haloalkoxy” radicals. Examples ofsuch radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term “partially or fully saturated” as used herein, refers to amoiety, linear, branched or cyclic in nature, having no atom-atom doubleor triple bonds (fully saturated) or having one or more atom-atom doubleor triple bonds which are arranged such that where the structural moietyis cyclic, the cycle is not fully unsaturated (non-aromatic), asappreciated by those skilled in the art.

The term “fully unsaturated” as used herein, refers to a moiety havingdouble or triple bonds, arranged in a manner such that the structure isaromatic in nature, as appreciated by those skilled in the art.

The term “aryl”, alone or in combination, means a carbocyclic aromaticmoiety containing one, two or even three rings wherein such rings may beattached together in a fused manner. Thus the term “aryl” embracesaromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl,anthracenyl, and indanyl. Said “aryl” group may have 1 or moresubstituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro,cyano, alkoxy and lower alkylamino, and the like. Phenyl substitutedwith —O—CH₂—O— forms an aryl benzodioxolyl substituent. Aryl as usedherein, implies a fully unsaturated ring.

The term “heterocycles” or “heterocyclic radicals”, alone or incombination, embraces saturated, partially saturated and partiallyunsaturated heteroatom-containing ring radicals, where the heteroatomsmay be selected from nitrogen, sulfur and oxygen. This term does notinclude rings containing —O—O—, —O—S— or —S—S— portions. Said“heterocycle” may have 1 or more substituents such as hydroxyl, Boc,halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy,amino and lower alkylamino.

Examples of saturated heterocyclic radicals include saturated 3 to6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated (or partiallyunsaturated) heterocyclyl radicals include dihydrothienyl,dihydropyranyl, dihydrofuryl and dihydrothiazolyl.

The term “heteroaryl” radicals, alone or in combination, embraces fullyunsaturated heteroatom-containing ring radicals, where the heteroatomsmay be selected from nitrogen, sulfur and oxygen. Examples of heteroarylradicals include unsaturated 5 to 6 membered heteromonocyclyl groupcontaining 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl,pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic groupcontaining an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.;unsaturated 5 to 6-membered heteromonocyclic group containing a sulfuratom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl[e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl];unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl].

The terms “heterocycle” and “heteroaryl” also embraces radicals whichare fused/condensed with aryl radicals: unsaturated condensedheterocyclic or heteroaryl groups containing 1 to 5 nitrogen atoms, forexample, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturatedand unsaturated condensed heterocyclic group containing 1 to 2 oxygen orsulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Examples ofheterocyclic radicals include five to ten membered fused or unfusedradicals. Further examples of beteroaryl radicals include quinolyl,isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl,and pyrazinyl. Other examples of heteroaryl radicals are 5- or6-membered heteroaryl, containing one or two heteroatoms selected fromsulfur, nitrogen and oxygen, such as thienyl, furyl, pyrrolyl,indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl radicals.

Examples of non-nitrogen containing heteroaryl include, withoutlimitation, pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl,benzothienyl, and the like.

Examples of partially and fully saturated heterocyclyl include, withoutlimitation, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isotbiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

The term “sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals —SO₂—.

The term “carbonyl”, whether used alone or with other terms, such as“aminocarbonyl”, denotes —(C═O)—.

The term “alkylthio” or “thioalkyl” embraces radicals containing alinear or branched alkyl radical, of one to ten carbon atoms, attachedto a divalent sulfur atom. An example of “alkylthio” is methylthio,(CH₃S—).

The term “aminoalkyl” and “diaminoalkyl” embraces “N-alkylamino” and“N,N-dialkylamino”, respectively, where amino groups are independentlysubstituted with one alkyl radical and with two alkyl radicals,respectively. Examples of alkylamino radicals include “lower alkylamino”radicals having one or two alkyl radicals of one to six carbon atoms,attached to a nitrogen atom. Suitable alkylamino radicals may be mono ordialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino and the like.

The term “C₁₋₁₀alkyl-amino-” denotes amino groups, which have beensubstituted with one or two alkyl radicals, such as N-methylamino. Thealkylamino radicals may be further substituted on the alkyl portion ofthe radical.

The term “aryl-alkyl-amino-” or “aralkylamino” denotes amino groups,which have been substituted with one or two aryl-substituted-alkylradicals, such as benzyl-amino. The aralkyl-amino radicals may befurther substituted on the aryl or alkyl portion of the radical.

The term “heterocyclyl-alkyl-amino-” denotes amino groups, which havebeen substituted with one or two heterocyclyl-substituted-alkylradicals, such as piperidyl-methyl-amino. The heterocyclyl-alkyl-aminoradicals may be further substituted on the heterocycle or alkyl portionof the radical.

The term “heteroaryl-alkyl-amino-” or “heteroaralkylamino” denotes aminogroups, which have been substituted with one or twoheteroaryl-substituted-alkyl radicals, such as pyrimidyl-amino. Theheteroaralkyl-amino radicals may be further substituted on theheteroaryl or alkyl portion of the radical.

The term “arylamino” denotes amino groups, which have been substitutedwith one or two aryl radicals, such as N-phenylamino. The arylaminoradicals may be further substituted on the aryl ring portion of theradical.

The term “heteroarylamino” denotes amino groups, which have beensubstituted with one or two heteroaryl radicals, such as N-thienylamino.The “heteroarylamino” radicals may be further substituted on theheteroaryl ring portion of the radical.

The term “cycloalkyl” includes saturated carbocyclic groups. Examples ofcycloalkyl groups include C₃-C₆ rings, such as compounds including,cyclopentyl, cyclopropyl, and cyclohexyl.

The term “cycloalkenyl” includes carbocyclic groups having one or morecarbon-carbon double bonds including “cycloalkyldienyl” compounds.Examples of cycloalkenyl groups include C₃-C₆ rings, such as compoundsincluding, without limitation, cyclopentenyl, cyclopentadienyl,cyclohexenyl and cycloheptadienyl.

The term “comprising” is meant to be open ended, including the indicatedcomponent(s) but not excluding other elements.

The terms “Formula I”, “Formula II”, “Formula III” and “Formula IV”include any sub formulas.

The present invention comprises processes for the preparation of acompound of Formulae I, II, III and IV.

Also included in the family of compounds of Formulas I-IV are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formulas I-IV may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsinclude, without limitation, hydrochloric, hydrobromic, hydroiodic,nitric, carbonic, sulfuric and phosphoric acid. Examples of organicacids include, without limitation, aliphatic, cycloaliphatic, aromatic,arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organicacids, examples of which are formic, acetic, adipic, butyric, propionic,succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic,β-hydroxybutyric, salicylic, galactaric and galacturonic acid.

Suitable pharmaceutically-acceptable base addition salts of compounds ofFormulas I-IV include, without limitation, metallic salts such as saltsmade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc, or salts made from organic bases including primary, secondary,tertiary amines and substituted amines including cyclic amines such ascaffeine, arginine, diethylamine, N-ethyl piperidine, aistidine,glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine,piperazine, piperidine, triethylamine, trimethylamine. All of the saltscontemplated herein may be prepared by conventional means from thecorresponding compound by reacting, for example, the appropriate acid orbase with the compound of Formulas I-IV. When a basic group and an acidgroup are present in the same molecule, a compound of Formulas I-IV mayalso form internal salts.

General Synthetic Procedures

The compounds of the invention can be synthesized according to thefollowing procedures of Schemes 1-8, wherein the substituents are asdefined for Formulas I-IV, above, except where further noted. Thesynthetic methods described below are merely exemplary, and thecompounds of the invention may be synthesized by alternate routes asappreciated by persons of ordinary skill in the art.

The following list of abbreviations, used throughout the specificationrepresent the following:

-   ACN, AcCN, MeCN—acetonitrile-   BSA—bovine serum albumin-   Cs₂CO₃—cesium carbonate-   CHCl₃—chloroform-   CH₂Cl₂, DCM—dichloromethane, methylene chloride-   DIBAL—diisobutylaluminum hydride-   DIEA, (iPr₂Net)—diisopropylethylamine-   DME—dimethoxyethane-   DMF—dimethylformamide-   DMAP—4-dimethylaminopyridine-   DMSO—dimethylsulfoxide-   dppa—diphenylphosphoryl azide-   EDC—1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   Et₂O—diethyl ether-   EtOAc ethyl acetate-   FBS—fetal bovine serum-   g, gm—gram-   h, hr—hour-   HBr—hydrobromic acid-   HCl—hydrochloric acid-   HOBt—1-hydroxybenzotriazole hydrate-   H₂—hydrogen-   H₂O₂—hydrogen peroxide-   HATU—O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate-   HPLC—high pressure liquid chromatography-   IPA, IpOH—isopropyl alcohol-   K₂CO₃—potassium carbonate-   MCPBA—meta-chloroperbenzoic acid-   MgSO₄— magnesium sulfate-   MeOH—methanol-   N₂— nitrogen-   NaHCO₃-sodium bicarbonate-   NaOH—sodium hydroxide-   NaH—sodium hydride-   Na₂SO₄— sodium sulfate-   NH₄Cl—ammonium chloride-   NH₄OH—ammonium chloride-   NMP—N-methylpyrrolidinone-   P(t-bu)₃—tri(tert-butyl)phosphine-   PBS—phospate buffered saline-   Pd/C—palladium on carbon-   Pd(PPh₃)₄—palladium(0)triphenylphosphine tetrakis-   Pd(PhCN)₂Cl₂—palladium di-cyanophenyl dichloride-   Pd(OAc)₂— palladium acetate-   Pd₂(dba)₃—bis(dibenzylideneacetone) palladium-   PyBop—benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium    hexafluorophosphate-   RT, rt—room temperature-   RBF—round bottom flask-   rac-BINAP—2,2′-Bis(diphenylphosphine)-1,1′-binaphthyl-   TBTU—O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   TEA, Et₃N—triethylamine-   TFA—trifluoroacetic acid-   THF—tetrahydrofuran

Compounds 5 of Formula I-IV (where L1 is O and L2 is NH), can beprepared according to the method generally described in Scheme 1. Asshown, a base assisted nucleophilic displacement reaction by a compound2 of an aryl halide 1 (where the halide as shown is chloride, and whereD′ may be an optionally substituted 5- or 6-membered aromatic ring)should generally afford amino intermediate 3. Starting compounds 1 maybe commercially available or prepared using methods described in theExamples below or by known techniques in the art. The alcohol 2 isgenerally sufficiently nucleophilic, under suitable conditions, todisplace the chloride of compound 1. Compound 2 may also be a thiol, aprimary or secondary amine or a nucleophilic carbon species (all ofwhich are not shown) to effect the transformation to compound 3, asappreciated by those skilled in the art. The amine group on compound 2may be protected as necessary or left unprotected, as appreciated bythose skilled in the art. Suitable bases to yield compound 3 include,without limitation, carbonate bases such as cesium carbonate (Cs₂CO₃),Na₂CO₃, K₂CO₃ and the like in a suitable solvent, whose properties willgenerally depend upon the solubility of the starting materials,polarity, and other factors readily appreciated in the art. Amine 3, ifprotected may generally first be deprotected, and then reacted with anoptionally substituted chloro-pyridine, chloro-pyridazine (where A⁸ isN), chloro-phthalazine (where R⁷ and R⁸ taken together form a phenylring) and the like under suitable conditions, including withoutlimitation, under basic conditions (Method B4), acidic conditions(Method B1 (TFA) or Method B2 (pTsOH and HCl) and heated conditions(Method B3), in suitable solvent or combination of solvents to affordcompound 5, of Formula I. It should be understood that compound 5 mayalso be a compound with formulas II, III and IV described herein.Representative examples of such reactions are further describedhereinbelow.

The strategy for preparing compounds 5, as exemplified in scheme 1, maygenerally be approached by building and/or broken down 2 primary linkingbonds, i.e., the connections of both L¹ and L². Thus, compounds 7(similar to compounds 5 but having R⁷ and R⁸ taken together to form aphenyl ring, as in Formula IV herein) may alternatively be preparedaccording to the method shown in scheme 2 below.

Compounds 7 of Formulas I-IV (where L¹ is O and L² is NH), can beprepared according to the method generally described in Scheme 2. Asshown, a nucleophilic displacement reaction by a compound 2 of an arylhalide 4 (where the halide as shown is chloride) should generally affordhydroxy intermediates 6. Such reaction may optionally be run in thepresence of acid to afford compounds 6. Starting compounds 1 may bereacted with alcohols 6, under suitable conditions such as thoseconditions described in scheme I above or the Examples herein (MethodsC1-C7), to afford compounds 7. As mentioned in scheme 1, compound 2 mayalso be a thiol, a primary or secondary amine or a nucleophilic carbonspecies (all of which are not shown) to effect the transformation tocompound 7, as appreciated by those skilled in the art. In the eventcompound 2 is a thiol, the reaction may be accomplished without the needfor acidic or basic conditions, and may also be accomplished at ambienttemperatures, as appreciated by those skilled in the art. Representativeexamples of such reactions are further described hereinbelow. Suitabletransformation methods are known to those skilled in the art, and aregenerally described in Jerry March's Advanced Organic Chemistry, 4^(th)edition (1992), which disclosure is hereby incorporated by reference inits entirety.

Compounds 10 can be made by treating compounds 8 (where L¹ is as definedherein) with either of reagents 9 in a Suzuki (Method A1), Stille(Method A2) or Sonagashira (Method A3) type reaction, under conditionssuitable for each reaction, respectively, as shown in scheme 3 (alsoreferred to herein as General Method A). Such reactions work well whereR⁶ is an aromatic group. Each reaction method is known in the art andgenerally appreciated by those skilled in the art. Examples of suchreactions are described in further detail hereinbelow. In addition,methods for Sonagashira reactions may be found in Angew. Chem. Int. Ed.2003, 42, 5993-5996. Ether linked R⁶ groups may also be installed ontochloro-phthtalazines 8 using a base, such as cesium carbonate (MethodA4) under suitable light conditions, such as irradiation, to affordcompounds 10. Amine linked R⁶ groups may also be afforded ontophthalazines 8 using heat (Method A5) in the presence of a suitableamine, such as piperidine, to provide compounds 10.

The method of scheme 3 allows desired R⁶ groups to be the final step ofsynthesis of compounds 10. Care must be taken to restrict the R¹, R⁷ andR⁸ in this method to those groups, which would not interfere with orreact under suitable reaction method and/or conditions to form compounds10, as appreciated by persons of ordinary skill in the art.

Compounds 13 may be prepared by a single reaction between abromo-substituted compound 11 and a desired R¹ group appropriatelysubstituted with a nucleophile or other suitable group to preparecompound 13. Such transformations may be accomplished using a variety ofdifferent methods, as appreciated by those skilled in the art. Forexample, desirable amino-R¹ groups can be installed at a suitableposition on a D′ ring by treating bromide 11 in the presence of asuitable palladium species and a suitable R¹-halide, R¹-amine or otherdesired R¹-reagent under suitable conditions. For example, modifiedSuzuki conditions involving the use of a Pd(0) mediated-coupling with anaryl boronate in the presence of mild base, such as sodium or potassiumcarbonate or bicarbonate, in toluene may also afford compounds 13.Compounds 13 can also be prepared using corresponding stannanes orzincates, as is known in the art. Alternatively, desired R¹ groups maybe installed onto the D′-ring using conventional methods (not shown), asappreciated by those skilled in the art.

The Examples described hereinafter represent exemplary methods ofsynthesizing or preparing desired compounds of Formulas I-IV,intermediates and various starting materials and/or building blocksthereof. It should be appreciated that these methods are merelyrepresentative examples and other conventional, known or developedalternative methods may also be utilized. It should also be appreciatedthat the exemplary compounds are merely for illustrative purposes onlyand are not to be construed as limiting the scope of the presentinvention in any manner.

Analytical Methods:

Unless otherwise indicated, all HPLC analyses were run on a AgilentModel 1100 system with an Agilent Technologies Zorbax SB—C₈(5μ) reversephase column (4.6×150 mm; Part no. 883975-906) run at 30° C. with a flowrate of about 1.50 mL/min. The mobile phase used solvent A (H₂O/0.1%TFA) and solvent B (AcCN/0.1% TFA) with a 11 min gradient from 5% to100% AcCN. The gradient was followed by a 2 min return to 5% AcCN andabout a 2.5 minute re-equilibration (flush).

LC-MS Method:

Samples were run on a Agilent model-1100 LC-MSD system with an AgilentTechnologies XDB-C₈(3.5 p) reverse phase column (4.6×75 mm) at 30° C.The flow rate was constant and ranged from about 0.75 mL/min to about1.0 mL/min.

The mobile phase used a mixture of solvent A (H₂O/0.1% HOAc) and solventB (AcCN/0.1% HOAc) with a 9 min time period for a gradient from 10% to90% solvent B. The gradient was followed by a 0.5 min period to returnto 10% solvent B and a 2.5 min 10% solvent B re-equilibration (flush) ofthe column.

Preparative HPLC Method:

Where indicated, compounds of interest were purified via reverse phaseHPLC using a Gilson workstation with a 30×50 mm column at 40 mL/min. Themobile phase used a mixture of solvent A (H₂O/0.1% TFA) and solvent B(AcCN/0.1% TFA) with a 15 min gradient from 10% to 95% solvent B. Thegradient is followed by a 2 min return to 10% AcCN.

Proton NMR Spectra:

Unless otherwise indicated, all ¹H NMR spectra were run on a Varianseries Mercury 300 MHz or on a Bruker 400 MHz instrument. Where socharacterized, all observed protons are reported as parts-per-million(ppm) downfield from tetramethylsilane (TMS) or other internal referencein the appropriate solvent indicated.

EXAMPLE 1

Synthesis of 3-bromo-8-chloro-1,5-naphthyridine Step 1: Diethyl2-((5-bromonyridin-3-ylamino)methylene)malonate

To a 500 mL RBF containing 5-bromopyridin-3-amine (60.0 g, 347 mmol) wasadded diethyl 2-(ethoxymethylene)malonate (71.0 mL, 354 mmol) and 121 mLof toluene. The reaction mixture was heated to reflux for 3 h. Thereaction mixture was allowed to cool RT overnight, and the resultingprecipitate was collected by filtration and dried to give the desiredproduct as a white crystalline solid.

Step 2: Ethyl 7-bromo-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate

In a RBF fitted with a reflux condenser a mixture of diethyl2-((5-bromopyridin-3-ylamino)methylene)malonate (1 g, 3 mmol) and1-phenoxybenzene (10 mL, 63 mmol) was heated to reflux for 1 h. Thereaction mixture was allowed to cool to RT and CH₃CN was added. Theresulting solids were filtered and dried to provide the desired productas a light brown solid.

Step 3: 7-bromo-4-hydroxy-1,5-naphthyridine-3-carboxylic acid

Ethyl 7-bromo-4-oxo-1,4-dihydro-1,5-naphtyridine-3-carboxylate (1 g, 3mmol) and 2.5 M NaOH (10 mL) were refluxed for 1 h in a RBF fitted witha reflux condenser. The hot, heterogeneous mixture was diluted withboiling water at which point a tan precipitate dissolved. Charcoal wasadded to the solution, which was swirled for 2 min and then the mixturewas filtered. Glacial acetic acid was added to the filtrate and a whiteprecipitate started to form (pH adjusted to 4). The precipitate wasfiltered off upon cooling, washed with water and dried to provide thedesired product as a white solid.

Step 4: 7-bromo-1,5-naphthyridin-4-ol

In a RBF fitted with a reflux condenser,7-bromo-4-hydroxy-1,5-naphthyridine-3-carboxylic acid (1 g, 4 mmol) wasadded in portions over 10 minutes to stirred refluxing quinoline (50mL), and the resulting mixture was refluxed for 1 h. The mixture wascooled and diluted with acetone. The precipitate was filtered, washedwith water and dried to give 0.8 g of a grey-brown powder. The productwas reprecipitated from aq. NaOH with glacial acetic acid to give awhite solid.

Step 5: 3-bromo-8-chloro-1,5-naphthyridine

7-Bromo-1,5-naphthyridin-4-ol (7.0 g) and phosphoryl chloride (200 mL)were refluxed for 5 h in a RBF fitted with a reflux condenser. ExcessPOCl₃ was distilled off under reduced pressure and the residue pouredonto ice. This cold mixture was carefully neutralized with aq. ammonia,which caused an exotherm. The resulting solid was filtered, washed withwater and dried. The product was recrystallized from n-heptane to givewhite needles of 3-bromo-8-chloro-1,5-naphthyridine.

EXAMPLE 2

Synthesis of 7-Methoxy-1H-[1,6]naphthyridin-4-one Step 1:4-amino-3-bromo-2-chloropyridine

4-Amino-2-chloropyridine (50 g, 388 mmol) was dissolved in glacialacetic acid (500 mL). To this solution was added NBS (75 g, 426 mmol)portionwise at RT (water bath cooling was provided to control theexothermicity). The reaction mixture was stirred at RT for 1 h at whichpoint the reaction was found complete (as monitored by TLC). Solvent wasremoved under reduced pressure followed by azeotropic distillation withethanol. The crude product was purified by column chromatography onsilica gel (230-400 mesh) eluting with ethyl acetate hexane mixture.

Step 2: 4-amino-3-bromo-2-methoxypyridine

Methanol (350 mL) was charged in a two-neck RBF equipped with a guardtube and septum and cooled to 0° C. Sodium metal (23 g) was added to itslowly in pieces. After all sodium metal had dissolved,4-amino-3-bromo-2-chloro pyridine (23 g, 178 mmol) was added and thesolution was heated at 180° C. in a pressure vessel for 5-6 h. Thereaction mixture was then cooled to 0° C. and adjusted to pH 8 byaddition of conc. HCl. Solvent was removed under reduced pressure andthe residue was suspended in ethyl acetate. Undissolved impurities wereremoved by filtration and the filtrate was concentrated under reducedpressure to obtain pure product.

Step 3:5-[(3-Bromo-2-methoxy-pyridin-4-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione

A two necked RBF equipped with a reflux condenser was charged withMeldrum's acid (15.6 g, 108 mmol) and trimethyl orthoformate (143 mL).The reaction mixture was heated 100° C. for 2 h.4-amino-3-bromo-2-methoxypyridine (22 g, 108 mmol) was added and heatingwas continued for an additional 4 h at 100° C. The reaction mixture wasallowed to cool to RT, diluted with hexane and filtered to obtain theproduct as a yellow solid.

Step 4: 8-Bromo-7-methoxy-1H-[1,6]naphthyridin-4-one

A two neck RBF equipped with an air condenser was charged with5-[(3-Bromo-2-methoxy-pyridin-4-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione(23 g, 64 mmol) and diphenyl ether (230 mL). The reaction mixture washeated at 250° C. for 30 min under nitrogen atmosphere after which itwas cooled to RT, diluted with hexane and filtered to obtain a darksolid. The crude product was refluxed in hexane for 30 min and filteredto obtained 8-Bromo-7-methoxy-1H-[1,6]naphthyridin-4-one as a brownsolid.

Step 5: 7-Methoxy-1H-[116]naphthyridin-4-one

8-Bromo-7-methoxy-1H-[1,6]naphthyridin-4-one (12 g, 33.5 mmol) wasdissolved in anhydrous methanol (240 mL) and 10% Dry Pd/C (2.4 g) wasadded carefully in portions. This was followed by portionwise additionof ammonium formate (24 g) which caused an exotherm. The reactionmixture was heated to reflux for 1 h. The reaction mixture was cooled toRT, filtered through Celite, and washed with hot MeOH. The filtrate wasconcentrated and the residue purified by column chromatography on silicagel (230-400 mesh) eluting with ethyl acetate-methanol.

Step 6: 4-Chloro-7-methoxy-[1,6]naphthyridine

A two neck RBF equipped with CaCl₂ guard tube was charged with7-Methoxy-1H-[1,6]naphthyridin-4-one (28 g, 159 mmol) and POCl₃(280 mL).The reaction mixture was stirred at RT for 3 h. The reaction mixture waspoured into ice water and the pH was carefully adjusted to 8 with solidsodium carbonate (highly exothermic reaction). The product was extractedwith EtOAc. The combined organic layer was washed with water, dried overNa₂SO₄ and concentrated. The crude product was purified by columnchromatography on silica gel (230-400 mesh) eluting with ethyl acetatehexane mixture.

EXAMPLE 3

Synthesis of 8-chloro-3-methoxy-1,5-naphthyridine Step 1:3-Bromo-5-methoxypyridine

Sodium (12 g) was dissolved in methanol (150 mL) while cooling, andexcess MeOH was removed under reduced pressure to obtain NaOMe, whichwas azeotroped with toluene (2×100 mL). A solution of3,5-dibromopyridine (100 g) in DMSO (500 mL) was added to sodiummethoxide and the mixture was stirred at 90° C. for 2 h. After coolingto RT, aqueous NaOH solution (3 M, 300 mL) was added and the mixture wasextracted with Et₂O. The ethereal layer was washed with brine and driedover Na₂SO₄. After concentration the crude product obtained was purifiedby flash column chromatography (Hexane:EtOAc 85:15) to afford pureproduct 3-bromo-5-methoxy pyidine.

Step 2: 3-amino-5-methoxypyridine

3-Bromo-5-methoxypyridine (15 g) was added to a pressure vessel, andCuSO₄(3.9 g) and 25% aq. ammonia (150 mL) were added. The reactionmixture was stirred for 4 h at 135° C., then cooled to RT, basified withaqueous NaOH solution, and extracted with CH₂Cl₂. After evaporation ofvolatiles, 3-amino-5-methoxypyridine was obtained as yellow solid.

Step 3:5-[(5-Methoxy-pyridin-3-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione

A two-necked RBF equipped with a reflux condenser was charged withMeldrum's acid (14.4 g, 100 mmol) and trimethylorthoformate (100 mL).The reaction mixture was heated at 100-105° C. for 2 h.5-amino-3-methoxy pyridine (12.5 g, 100 mmol) was added to the reactionmixture and heating was continued for an additional 4 h at the sametemperature. The reaction mixture was allowed to cool to RT, dilutedwith hexane and filtered to obtain the product as light yellow solid.

Step 4: -Methoxy-1H-[1,5]naphthyridin-4-one

A two-necked RBF equipped with an air condenser was charged with5-[(5-Methoxy-pyridin-3-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione(18 g) and diphenyl ether (180 mL). The reaction mixture was heated at240-250° C. for 5 min under N₂ atmosphere after which it was cooled toRT, diluted with hexane and filtered to obtain a dark solid. The crudeproduct was refluxed in hexane for 30 min and filtered to obtain productas a brown solid.

Step 5: 8-chloro-3-methoxy-1,5-naphthyridine

A two-necked RBF equipped with an air condenser (protected with CaCl₂guard tube) was charged with 7-Methoxy-1H-[1,5]naphthyridin-4-one (13 g)and POCl₃(65 mL). The reaction mixture was allowed to reflux at 120° C.for 12 h. The POCl₃ was removed in vacuo and azeotroped twice withtoluene. EtOAc (75 mL) was added and the reaction mixture was stirred at50-60° C. for 15-20 min. EtOAc removed separated by decantation. Theorganic layers were combined and concentrated. The obtained crude wasdissolved in EtOAc (50 ml) and a washed with satd. aqueous sodiumbicarbonate. The organic layer was dried over Na₂SO₄ and concentrated.The resulting solids were suspended in hexane, stirred for 15 min,filtered and dried under vacuum.

EXAMPLE 4

Synthesis of 8-Chloro-2-methoxy-1,5-naphthyridine Step 1:5-((6-Methoxypyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

A mixture of Meldrum's acid (34.8 g, 0.242 mol) and trimethylorthoformate (285 mL, 2.05 mol) was heated to 105° C. for 2 h. To thesolution 6-methoxypyridin-3-amine (30 g, 0.242 mol) was added andcontinued the stirring overnight at the same temperature. The mixturewas allowed to cool to RT and diluted with hexane. The solidprecipitated was filtered and washed with hexane to afford5-((6-methoxypyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dioneas a pale yellow solid.

Step 2: 6-Methoxy-1,5-naphthyridin-4(1H)-one

A suspension of5-((6-methoxypyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione(51.3 g, 0.185 mol) in diphenylether (1275 mL) was heated to 250° C.under nitrogen atmosphere for 20 min. The reaction mixture was cooled toRT and diluted with hexane. The gummy solid was then triturated withhexane to obtain 6-methoxy-1,5-naphthyridin-4(1H)-one as a pale browncolor solid.

Step 3: 8-Chloro-2-methoxy-1,5-naphthyridine

To the intermediate 6-methoxy-1,5-naphthyridin-4(1H)-one (15.0 g, 0.085mol) was added POCl₃(300 mL) dropwise under nitrogen atmosphere at RT.The reaction mixture was heated to 110° C. with constant stirring. After12 h, the mixture was concentrated in vacuo and azeotroped with toluene(2×100 mL). The residue was dissolved in ice-water (100 mL) and adjustedpH of the solution to 7 using 10% NaHCO₃ solution, and extracted withEtOAc (4×100 mL). The combined organic extracts were washed with water(2×100 mL), saturated NaCl solution (100 mL), dried (Na₂SO₄), filteredand concentrated in vacuo.

EXAMPLE 5

Synthesis of 4-Chloro-1H-pyrrolo[2,3-b]pyridine Step 1:1H-Pyrrolo[2,3-b]pyridine

The title compound was prepared according to a procedure described inWO2003082289A1. A solution of 1H-pyrrolo[2,3-b]pyridine (10.0 g, 84.6mmol) in ethyl acetate (846 ml, 84.6 mmol) was cooled to 0° C. To thecold solution was added a solution of mCPBA (103 mmol, 23.1 g, 77% pure)in 53 mL of EtOAc over a period of 1.5 h. Halfway into the reaction, 100mL of EtOAc was added to the reaction to ease stirring of the thickmixture. The residual mCPBA was washed into the reaction mixture by anadditional portion of EtOAc (25 mL). Solid precipitated out of thesolution, and the resulting mixture was warmed to rt, and allowed tostir at this temp until the starting azaindole had been consumed asjudged by RPLC. After 3 h at rt, the reaction was completed. Thereaction mixture was cooled back to 0° C. The resulting slurry wasfiltered to collect the N-oxide as the meta-chlorobenzoic acid salt. Thesolid was washed with additional EtOAc and dried under vacuum. Theproduct, 1H-pyrrolo[2,3-b]pyridine 1-oxide salt of mCBA was obtained aslight yellow solid.

The mCBA salt was treated with aqueous base to liberate the N-oxide. Aslurry of the N-oxide mCBA salt (35.5 g, 265 mmol) in 149 mL ofdeionized water at 15° C. was treated with sufficient amount of aqueoussolution containing 30% by weight of potassium carbonate (11.0 g, 79.4mmol) to raise the pH of the slurry between 9.5 to 10.5. Additionalwater (74 mL) was added to the mixture while the temperature wasmaintained between 15° C. to rt for 2 h. The slurry was cooled to 0° C.for 5 h, and then filtered to recover the precipitate. The precipitatewas washed with water and dried to afford the white N-oxide product,1H-pyrrolo[2,3-b]pyridine 1-oxide. ¹H NMR (Bruker, 400 MHz, DMSO-d6)12.0 (br s, 1H), 8.19 (d, J=5.4 Hz, 1H), 7.60 (t, J=3.0 Hz, 1H), 7.20(d, J=5.0 Hz, 1H), 6.52 (d, J=3.0 Hz, 1H).

Step 2: 4-Chloro-1H-pyrrolo[2,3-b]pyridine

The title compound was prepared according to a procedure describedWO03/082289 A1. A solution of azaindole N-oxide (6.82 g, 51.0 mmol) inDMF (36.0 ml, 470 mmol) was heated to 50° C. Methanesulfonyl chloride(11.0 ml, 137 mmol) was added to the heated solution at such a rate asto maintain the reaction temperature at 65 to 75° C. The resultingmixture was heated at 68-77° C. until the reaction was judged completeby RPLC. The total reaction time was 4 h. The reaction was cooled to rtand quenched with water (10 mL). The mixture was cooled to 5° C. 10 NNaOH solution was added to raise the pH of the solution to 7. Theresulting slurry was warmed to rt, agitated for 1 h, and then filteredto collect the product. The product was washed with additional water anddried under vacuum. Rusty solid, 4-chloro-1H-pyrrolo[2,3-b]pyridine wascollected. ¹H NMR (Bruker, 400 MHz, DMSO-d6) 12.0 (br s, 1H), 8.19 (d,J=5.4 Hz, 1H), 7.60 (t, J=3.0 Hz, 1H), 7.20 (d, J=5.0 Hz, 1H), 6.52 (d,J=3.0 Hz, 1H).

EXAMPLE 6

Synthesis of 4-Bromo-6,7-dimethoxycinnoline Step 1:6,7-Dimethoxycinnolin-4-ol

1-(2-Amino-4,5-dimethoxyphenyl)ethanone (105 g, 0.538 mol) was dissolvedin concentrated HCl (2000 mL, 20 mol) at ambient temperature. Thesolution was then cooled to 0-4° C., and sodium nitrite (37.5 g, 0.543mol) was added dropwise over 45 minutes as a solution in water (200 mL).The reaction mixture was stirred at 0-4° C. for one hour during whichtime it turned dark brown and became homogenous. The reaction mixturewas then heated to 60-70° C. for four hours, and a yellow solid formed.After cooling the reaction mixture to 10° C., the solid was collected byfiltration. The wet solid was suspended in 1500 mL of water, and the pHwas adjusted to 12 with 4N NaOH to give a brown solution, followed byadjusting the pH to 7 with concentrated hydrochloric acid (78 mL).6,7-Dimethoxycinnolin-4-ol precipitated as an off-white solid, which wasfiltered, washed with water (3×300 mL), and dried in a vacuum overnightat 50° C.

Step 2: 4-Bromo-6,7-dimethoxycinnoline

Phosphorus oxybromide (125 g, 0.436 mol) was added to a suspension of6,7-dimethoxycinnolin-4-ol (65 g, 0.32 mol) in chloroform (550 mL, 6.9mol). The reaction mixture was stirred at 65° C. for 18 hours. Formationof a fine yellow solid was observed. The reaction mixture was pouredonto crushed ice (200 g), and the pH was adjusted to 6-7 with sodiumacetate (285 g) and sat. NaHCO₃. The organic layer was separated, andthe aqueous layer was extracted with dichloromethane (2×200 mL). Thecombined organic extracts were washed with brine (2×100 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo to provide a light tan oil.DCM (40 mL) and hexanes (250 mL) were added, and the resulting solid wasfiltered to provide 4-bromo-6,7-dimethoxycinnoline as an off-whitesolid.

EXAMPLE 7

Synthesis of7-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridine

To a mixture of lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate(2.125 g, 9.7 mmol) and DMF (20 drops) in CH₂Cl₂(35 mL), oxalyldichloride (1.3 ml, 15 mmol) was added dropwise. The mixture was stirredat RT for 2.5 h and then was concentrated to give a yellow solid. Theresultant crude acid chloride and (Z)-N′-hydroxyacetamidine (1.4 g, 19mmol) were heated at 140° C. in xylene/pyridine (6/1, 35 mL) for 1 h.The mixture was diluted with CH₂Cl₂, and then washed with water, thensat. NaHCO₃ and brine. The crude product was purified via columnchromatography on silica gel (RediSep 120 g column, gradient elutionwith 0-50% EtOAc in Hexane) to afford7-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridine as awhite solid.

EXAMPLE 8

Synthesis of (7-chlorothieno[3,2-b]pyridin-2-yl)(morpholino)methanone

[Lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (100 mg, 455 μmol)was dissolved in CH₂Cl₂(5 mL) with one drop of DMF and oxalyl chloride(2 mL) was added. The mixture was stirred at RT for one hour thenconcentrated and dried under high vacuum. Morpholine (60 μl, 683 μmol)was then added to the mixture with N-ethyl-N-isopropylpropan-2-amine(238 μl, 1366 μmol) and the mixture was stirred for 20 hours. The mixwas then concentrated and purified using 0 to 100% 90/10/1CH₂Cl₂/MeOH/ammonium hydroxide in CH₂Cl₂ to afford(7-chlorothieno[3,2-b]pyridin-2-yl)(morpholino)methanone.

EXAMPLE 9

Synthesis of 7-chlorothieno[3,2-b]pyridine-2-carboxamide

A 250 mL flask was charged with lithium7-chlorothieno[3,2-b]pyridine-2-carboxylate (3.00 g, 13.7 mmol) andCH₂Cl₂(100 ml) under nitrogen. DMF (cat) (0.100 ml) and oxalyldichloride (1.49 ml, 17.1 mmol) were added dropwise, and the reactionmixture was stirred for 3 hours, and concentrated in vacuo. The brownsolid was redissolved in CH₂Cl₂(100 ml) and ammonia (gas) (0.233 g, 13.7mmol) was gently bubbled through the reaction mixture for 5 minutes. Theflask was then capped and stirred at room temperature overnight underclosed atmosphere. The brown suspension was concentrated in vacuo andthe resulting solid was taken up in water (to dissolve the startingmaterial), then collected by filtration to give7-chlorothieno[3,2-b]pyridine-2-carboxamide. MS m/z=213 [M+H]⁺. Calc'dfor C₈H₅ClN2₅OS: 212.66.

EXAMPLE 10

Synthesis of 4-Chloro-6,8-difluoro-quinoline Step 1:5-[(3,5-Difluoro-phenylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione

In a oven dried 2-neck RBF equipped with reflux condenser and inertatmosphere, meldrum's acid (30 g, 0.208 mole) was dissolved intriethylorthoformate (185 g, 1.25 mole) and the reaction mixture wasrefluxed at 100° C. under nitrogen for 1 h. On complete consumption ofstarting material (tic), 3,5-difluoroaniline (26.8 g, 0.208 mol) wasadded and the heating continued for 4 h. After completion of thereaction (tic), reaction mixture was brought to RT and diluted withhexane (300 ml) when yellow solid precipitated. The solid was filtered,washed thoroughly with hexane and dried to furnish the product.

Step 2: 4-Hydroxy-6,8-difluoro-quinoline

(5-[(3,5-Difluoro-phenylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione, (52 g, 0.1837 mol) was dissolved in diphenyl etherand refluxed for 20 min at 200° C. On complete consumption of startingmaterial (tic), reaction mixture was cooled and diluted by hexane. Solidobtained was filtered and washed with sufficient quantities of hexane tofurnish product. Mass: 182.09 (M+1).

Step 3: 4-Chloro-6,8-difluoro-quinoline

(4-Hydroxy-6,8-difluoro-quinoline, 29.1 g, 0.160 mol) was dissolved inPOCl₃(183 mL) and heated at reflux for 12 h. On complete consumption ofstarting material (tic) the contents were brought to RT and excess POCl₃was removed under reduced pressure. Crude mass was azeotroped withtoluene and product was diluted with ethyl acetate, organics were washedwith sodium bicarbonate and solvent removed under reduced pressure.Crude product was purified by column chromatography at 100-200 mesh sizesilica in 0-2% EtOAc-hexane. Mass: 199.99 (M+1).

EXAMPLE 11

The title compound was prepared in accordance with a procedure describedin PCT patent publication WO 2005047279, titled “Preparation ofquinoxazolines and related derivatives vanilloid-1 receptor antagonistsfor treating pain.”

EXAMPLE 12-a Method A4

4-Isopropoxy-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine

In a 5 mL sealed tube, was dissolved4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine(0.100 g, 0.224 mmol) in iPrOH (0.500 mL). To this was added cesiumcarbonate (0.110 g, 0.336 mmol) and the mixture was irradiated for 30min at 140° C. in the microwave. When the reaction was determined to becomplete by LC/MS, it was concentrated. The mixture concentrate waspurified using Isco silica gel chromatography, using 0-100%CH₂Cl₂:MeOH(90:10)/CH₂Cl₂, followed by reverse phase chromatography(Gilson, 10-90% TFA/acetonitrile in water over 15 min). Theproduct-containing fractions were extracted into DCM, washed 1× sodiumcarbonate, 1×H₂O, dried with Na₂SO₄, filtered through fritted funnel,and concentrated to yield4-isopropoxy-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amineas a light yellow solid. MS [M+H]⁺=470.0; Calc'd=469.6 for C₂₆H₂₃N₅O₂S

EXAMPLE 12-b Method A5

N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-(4-methoxypiperidin-1-yl)phthalazin-1-amine

A 15 ml sealed pressure tube was charged with4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine(120 mg, 0.269 mmol) and 4-methoxypiperidine (620 mg, 5.382 mmol), in0.3 ml of DMSO. The sealed tube was placed in a preheated oil bath at100° C. where it was stirred for 16 hours. The reaction was cooled toambient temperature, diluted with 2 ml of MeOH, and the solutionpurified using Gilson Reverse Phase HPLC. The fractions containing thedesired product was neutralized with saturated sodium bicarbonate andextracted with 10 ml of DCM (3×). The organics were dried over Na₂SO₄,filtered and the filtrate was concentrated in vacuo to affordN-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-(4-methoxypiperidin-1-yl)phthalazin-1-amineas a yellow solid. MS [M+H]⁺=525.

EXAMPLE 13

The title compound, 4-chloro-7-methoxyquinoline-6-carboxamide, wasprepared by a method described WO 00/050405, Application No. WO2000-GB579.

EXAMPLE 14

The title compound, 7-chlorothieno[3,2-b]pyridine, was prepared by amethod described in Ragan, J. A.; Raggon, J. W.; Hill, P. D.; Jones, B.P.; McDermott, R. E.; Munchhof, M. J.; Marx, M. A.; Casavant, J. M.;Cooper, B. A.; Doty, J. L.; Lu, Y. Org. Process Res. Dev. 2003, 7,676-683, and related references cited therein.

EXAMPLE 15

The title compound,7-chloro-2-(1-methyl-1H-imidazol-5-yl)thieno[3,2-b]pyridine, wasprepared by a method described in Ragan, J. A.; Raggon, J. W.; Hill, P.D.; Jones, B. P.; McDermott, R. E.; Munchhof, M. J.; Marx, M. A.;Casavant, J. M.; Cooper, B. A.; Doty, J. L.; Lu, Y. Org. Process Res.Dev. 2003, 7, 676-683.

EXAMPLE 16

Synthesis of 4-(7-methoxy-1,5-naphthyridin-4-yloxy)benzenamine

Five 20 mL microwave vials were each charged with 4-aminophenol (0.700mg, 33 mmol) and 3 equivalents of cesium carbonate in 6.0 ml of DMF. Themixture was stirred at RT for 10 minutes. Following addition of8-chloro-3-methoxy-1,5-naphthyridine (1 g, 26 mmol), the reactionvessels were capped and irradiated at 150° C. for 15 min in themicrowave, at which time the reaction was determined complete by LCMS.The mixture was allowed to cool to ambient temperature and material fromthe five vessels was combined. A deep brown solid crashed out withaddition of water. Filtered solids, washed with water and driedovernight in the vacuum oven to afford4-(7-methoxy-1,5-naphthyridin-4-yloxy)benzenamine as a brown solid.

Alternatively, the title compound may be prepared by the followingmethod: In a nitrogen purged sealed pressure vessel, dissolved4-aminophenol (0.617 g, 5.65 mmol) in DMF (0.030 L). Cesium carbonate(3.68 g, 11.3 mmol) was added and the mixture was stirred at RT for 5min. Added 8-chloro-3-methoxy-1,5-naphthyridine (1.00 g, 5.14 mmol),heated to 90° C., stirred for 17 h. The mixture was allowed to cool toRT and was concentrated. The crude material was triturated withmethanol, filtered, washed with methanol followed by water, and airdried to yield 4-(7-methoxy-1,5-naphthyridin-4-yloxy)benzenamine asbrown solid. MS [M+H]=268.1; Calc'd 267.3 for C₁₅H₁₃N₃O₂.

EXAMPLE 17

Synthesis of 4(7-methoxy-1,5-naphthyridin-4-ylthio)benzenamine

A RBF was charged with 4-aminothiophenol (161 mg, 1.285 mmol),8-chloro-3-methoxy-1,5-naphthyridine (250 mg, 1.285 mmol) and 5.2 mL ofDMF, and the mixture was stirred at RT for 45 min. The orange,heterogeneous mixture was diluted with EtOAc and washed with 1N NaHCO₃.The aqueous portion was extracted two additional times with EtOAc andthe combined organics were dried with MgSO₄, filtered and concentrated.The crude oil was concentrated twice from toluene to remove DMF and theresulting solids were dried under high vacuum to provide4-(7-methoxy-1,5-naphthyridin-4-ylthio)benzenamine as a tan solid. MSm/z=284 [M+H]⁺. Calc'd for C₁₅H₁₃N₃OS: 283.35.

EXAMPLE 18

Synthesis of 4(4(4-methylpiperazin-1-yl)phthalazin-1-ylamino)phenol

A mixture of 4-aminophenol (42 mg, 0.38 mmol),1-chloro-4-(4-methylpiperazin-1-yl)phthalazine (100 mg, 0.381 mmol), andTFA (29 μl, 0.38 mmol) was heated in 2-butanol (3 mL) in a sealed tubeat 90° C. overnight. Next day LC/MS shows completion of reaction. Thereaction was cooled and diluted with DCM. Aqueous sodium bicarbonate wasadded and the organic layer was collected. The aqueous layer wasneutralized with 1N HCl and the product was extracted with DCM. Theorganic layers were combined, dried over sodium sulfate, andconcentrated to afford4-(4-(4-methylpiperazin-1-yl)phthalazin-1-ylamino)phenol as solid brownmaterial. MS [M+H]=336.2. Calc'd for C₁₉H₂₁N₅O: 335.4.

EXAMPLE 19

Synthesis of 4(4(4-methoxyphenyl)phthalazin-1-ylamino)phenolhydrochloride

4-Aminophenol (340 mg, 3.1 mmol),1-chloro-4-(4-methoxyphenyl)phthalazine (837 mg, 3.1 mmol), andsec-butanol (12 mL, 3.1 mmol) were combined in a resealable tube andheated to 100° C. overnight. The reaction progress was monitored byLCMS, and upon completion, the orange reaction was cooled diluted withdiethyl ether. The resulting precipitate was filtered and washed withdiethyl ether, and the solid was dried in vacuo to provide4-(4-(4-methoxyphenyl)phthalazin-1-ylamino)phenol hydrochloride (1.17 g,100% yield) as an orange solid. MS [M+H]=344.0. Calc'd for C₁₉H₂₁N₅O:343.13.

EXAMPLE 20

Synthesis of 5(4-phenylphthalazin-1-ylamino)pyridin-2-ol

Step 1: A RBF was charged with 6-methoxypyridin-3-amine (155 mg, 1.25mmol), 1-chloro-4-phenylphthalazine (300 mg, 1.25 mmol), and 2-butanol(4 mL). The vessel was sealed and the mixture was stirred overnight at90° C. LC/MS shows completion of reaction. Reaction cooled to RT andpurified by silica gel chromatography (1-5% MeOH/DCM) to affordN-(6-methoxypyridin-3-yl)-4-phenylphthalazin-1-amine as tan solid. MS[M+H]=329.1. Calc'd for C₂₀H₆N₄O: 328.4.Step 2: In a 25 RBF was addedN-(6-methoxypyridin-3-yl)-4-phenylphthalazin-1-amine (290 mg, 0.88mmol), hydrobromic acid (2.4 mL, 44.2 mmol) and acetic acid (2.5 mL,43.3 mmol), and a reflux condenser open to air was fitted and the RBFwas heated to 130° C., while stirring, for 2 h. The reaction was cooledto RT, the mixture neutralized with 6N NaOH, upon which a yellow solidcrashed out. The yellow solid was filtered, washed with water, placed invacuum oven at 30° C. to dry, to afford5-(4-phenylphthalazin-1-ylamino)pyridin-2-ol, as light yellow solid. MS[M+H]=315.2. Calc'd for C₁₉H₁₄N₄O: 314.3.

EXAMPLE 21

Synthesis of 1-Chloro-4-(4-methylthiophen-2-yl)phthalazine

1,4-Dichlorophthalazine (1.40 g, 7.03 mmol),4-methylthiophen-2-ylboronic acid (999 mg, 7.03 mmol), and PdCl₂(DPPF)(721 mg, 985 μmol) were added into a sealed tube. The tube was purgedwith Argon. Then sodium carbonate (2.0 M in water) (7.74 ml, 15.5 mmol)and 1,4-dioxane (35.2 ml, 7.03 mmol) were added. The tube was sealed,stirred at RT for 5 min, and placed in a preheated oil bath at 110° C.After 1 h, LC-MS showed product and byproduct (double coupling), and SMdichlorophthalazine. The reaction was cooled to RT, filtered through apad of celite with an aid of EtOAc, concentrated, and loaded ontocolumn. The product was purified by column chromatography using Hex toremove the top spot, then 80:20 Hex:EtOAc to collect the product. Theproduct, 1-chloro-4-(4-methylthiophen-2-yl)phthalazine was obtained asyellow solid. LC-MS showed that the product was contaminated with asmall amount of SM dichlorophthalazine and biscoupling byproduct. MSm/z=261 [M+1]⁺. Calcd for C₁₃H₉ClN₂S: 260.12.

EXAMPLE 22

Synthesis of 1-Chloros(6-methylpyridin-2-yl)phthalazine Step 1:2-(Dimethylamino)isoindoline-1,3-dione

The title compound was prepared according to methods described in thefollowing papers: (a) Deniau, E.; Enders. D.; Couture, A.; Grandclaudon,P. Tetrahedron: Asymmetry 2003, 14, 2253. (b) Saito, Y.; Sakamoto, T.;Kikugawa, Y. Synthesis 2001, 221. (c) Deniau, E.; Enders, D. TetrahedronLett. 2000, 41, 2347. To a solution of isobenzofuran-1,3-dione (5.00 g,34 mmol) and N,N-dimethylhydrazine (2.9 ml, 37 mmol) in toluene (75 ml,34 mmol) in a RBF was added p-TsOH.H₂O (0.32 g, 1.7 mmol). A Dean-Starkapparatus and a condenser were attached to the RBF. The mixture wasrefluxed. After 4 h, LCMS showed mainly product. The reaction was cooledto RT. Toluene was removed under reduced pressure, and the crude wasdissolved in CH₂Cl₂, washed with sat NaHCO₃, water, and brine. Theorganic was dried over MgSO₄, filtered, and concentrated. Light yellowsolid was obtained. ¹H NMR showed mainly product,2-(dimethylamino)isoindoline-1,3-dione. MS Calcd for C₁₀H₁₀N₂O₂:[M]⁺=190. Found: [M+H]⁺=191.

Step 2:2-(Dimethylamino)-3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1-one

In a dry RBF, 2-bromo-6-methylpyridine (66 μl, 581 μmol) and THF (1211μl, 581 μmol) were added. The reaction was purged with argon, and cooledto −78° C. BuLi (244 μl, 610 μmol) was added via syringe. After 30 min,the anion was cannulated into a solution of2-(dimethylamino)isoindoline-1,3-dione (166 mg, 872 μmol) in 2 mL of THFpreviously submerged in a cold bath at −78° C. for 2 min (the startingmaterial precipitated out of the solution at low temp). After 15 min at−78° C., the temperature was warmed to −30° C. After 1 h, LCMS showedmainly product at 1.535 min. The reaction was quenched slowly with sat.NH₄Cl. The product was extracted with CH₂Cl₂. The organic layer waswashed with brine, dried over MgSO₄, filtered, and concentrated to givea yellow oil. The product was purified using 85:15 CH₂Cl₂:(90:10:1CH₂Cl₂:MeOH:NH₄OH). Viscous yellow oil was obtained. ¹H NMR showedmainly product,2-(dimethylamino)-3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1-one. MSCalcd for C₁₆H₁₇N₃O₂: [M]⁺=283. Found: [M+H]⁺=284.

Step 3: 4-(6-Methylpyridin-2-yl)phthalazin-1(2H)-one

The title compound was prepared according to a method described inSaito, Y.; Sakamoto, T.; Kikugawa, Y. Synthesis 2001, 2, 221.2-(Dimethylamino)-3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1-one(3.18 g, 11.0 mmol), EtOH (11.0 ml, 11.0 mmol), and hydrazine (5.30 ml,168 mmol) were added into a RBF fitted with a reflux condenser. Anitrogen balloon was attached on top of the condenser. The reaction wasrefluxed overnight. LCMS showed that the reaction was completed. Thereaction was cooled to rt. Off-white solid precipitated out of thesolution. Water was added and the mixture was cooled to 0° C. The solidwas filtered off with an aid of water and dried under vacuum. Whitesolid was obtained. LCMS of the solid showed product,4-(6-methylpyridin-2-yl)phthalazin-1(2H)-one. MS Calcd for C₁₄H₁₁N₃O:[M]⁺=237. Found: [M+H]⁺=238.

Step 4: 1-Chloro-4-(6-methylpyridin-2-yl)phthalazine

A dry RBF set up with stirring bar and reflux condenser was charged with4-(6-methylpyridin-2-yl)phthalazin-1(2H)-one (780 mg, 3.29 mmol) andPOCl₃(10.7 ml, 115 mmol). This was stirred under reflux for 18 h. ExcessPOCl₃ was removed under vacuum with an aid of toluene. The residue wascooled to 0° C. and basified with cold 6 N NaOH until pH=9.Occasionally, ice was added to keep the mixture cold to prevent thehydrolysis. Stirring, agitation, and sonication eventually provided asolid material at basic pH. The solids were filtered, washed with ampleamount of water and dried under vacuum to afford a white solid. MS Calcdfor C₁₄H₁₀ClN₃: [M]⁺=255. Found: [M+H]⁺=256.

EXAMPLE 23

Synthesis of 1-chloro-(octahydroisoquinolin-2(1H)-yl)phthalazine

A resealable pressure bottle was charged with 1,4-dichlorophthalazine(1258 mg, 6.28 mmol), decahydroisoquinoline (588 μl, 3.95 mmol),potassium carbonate (546 mg, 3.95 mmol) and DMSO (20 mL, 0.2 M).Reaction was stirred at 80° C. for 16 h, then cooled to RT and dilutedwith 5 mL of DMSO. The solution was purified by Gilson HPLC (10% to 90%CH₃CN/H₂O/0.1% TFA) to afford1-chloro-4-(octahydroisoquinolin-2(1H)-yl)phthalazine. MS [M+H]=302.1.Calcd for C₁₇H₂₀ClN₃: 301.8.

EXAMPLE 24

Synthesis of 3-chloro-6-(3-chlorophenyl)-4-ethylpyridazine Step 1:4-(3-chlorophenyl)-2-ethyl-2-hydroxy-4-oxobutanoic acid

A RBF was charged with 2-oxobutanoic acid (2.50 g, 24.5 mmol) and 3.2 mLof water and the mixture was cooled to 0° C. The acid was neutralized byslow addition of 20% aqueous KOH. 3′-chloroacetophenone (3.79 g, 24.5mmol) was added, followed by a 1.3 M solution of KOH (2.20 g, 39.2 mmol)in MeOH. The reaction mixture was stirred at 0° C. for 48 h. The mixturewas brought to pH 2 by dropwise addition of conc. H₂SO₄. The MeOH wasremoved in vacuo, and 25 mL of water was added. The heterogeneousmixture was filtered through Celite, and the filter cake was washed withwater and CH₂Cl₂. The layers of the filtrate were separated, and theaqueous portion was extracted with additional CH₂Cl₂. The combinedorganics were dried with MgSO₄, filtered and concentrated to a volume of25 mL. Hexane was added until the mixture became cloudy, and uponstanding a white crystalline solid formed. The mother liquor wasdecanted and the solids were washed with hexane and dried to provide4-(3-chlorophenyl)-2-ethyl-2-hydroxy-4-oxobutanoic acid as a whitecrystalline solid. MS m/z=279 [M+Na]⁺. Calc'd for C₁₂H₁₃ClO₄: 256.69.

Step 2: 6-(3-chlorophenyl)-4-ethylpyridazin-3(2H)-one

A RBF was charged with4-(3-chlorophenyl)-2-ethyl-2-hydroxy-4-oxobutanoic acid (2.78 g, 10.8mmol), hydrazine (0.510 ml, 16.2 mmol) and 11 mL of n-BuOH. A Dean-Starkapparatus fitted with a reflux condenser was attached, and the mixturewas heated under nitrogen at 130° C. for 15 h. Upon cooling aprecipitate formed, which was filtered, washed with cold EtOH, anddried. 6-(3-chlorophenyl)-4-ethylpyridazin-3(2H)-one was isolated as awhite solid. MS m/z=235 [M+H]⁺. Calc'd for C₁₂H₁₁ClN₂O: 234.68.

Step 3: 3-chloro-6-(3-chlorophenyl)-4-ethylpyridazine

A RBF was charged with 6-(3-chlorophenyl)-4-ethylpyridazin-3(2H)-one(1.50 g, 6.4 mmol) and phosphorus oxychloride (6.0 ml, 64 mmol). Hunig'sbase (1.2 ml, 7.0 mmol) was added to the mixture dropwise (slightlyexothermic). The flask was fitted with a reflux condenser and a nitrogeninlet and the mixture was heated at 110° C. for 3 h. Upon cooling thereaction mixture was poured onto ice. 6N NaOH was added dropwise untilpH 9 while keeping the mixture cold by gradual addition of ice. Thesolids were filtered, washed with water and dried to provide3-chloro-6-(3-chlorophenyl)-4-ethylpyridazine as a peach colored solid.MS m/z=253 [M]⁺. Calc'd for C₁₂H₁₀Cl₂N₂: 253.13.

EXAMPLE 25

Synthesis of 4(1,5-naphthyridin-4-ylthio)benzenamine

To a mixture of tetrakis(triphenylphosphine)palladium (188 mg, 163 μmol)and sodium methoxide (176 mg, 3251 μmol) was added a solution of4-(7-bromo-1,5-naphthyridin-4-ylthio)benzenamine (540 mg, 1625 μmol) inDMF (2 mL). The resealable tube was purged with argon, and the mixturewas heated to 100° for 1.5 h. The mix was diluted with ethyl acetate,washed with brine twice, dried with sodium sulfate, and concentrated.The residue was purified by silica gel chromatography using 1-10%MeOH:CH₂Cl₂ w/1% NH₄OH to provide4-(1,5-naphthyridin-4-ylthio)benzenamine. MS m/z=254 [M]⁺. Calc'd forC₁₄H₁₁N₃S: 253.32.

EXAMPLE 26

Synthesis of 4-(4-bromoisoquinolin-1-ylamino)phenol hydrochloride

A mixture of 4-aminophenol (225 mg, 2062 μmol) and4-bromo-1-chloroisoquinoline (500 mg, 2062 μmol) was heated insec-butanol (15 mL) in a sealed tube at 100° C. for 2 hours. TFA (477μl, 6186 μmol) was added and the reaction mixture was allowed to stir at100° C. overnight. LCMS analysis showed conversion to4-(4-bromoisoquinolin-1-ylamino)phenol hydrochloride. The dark redreaction mixture was cooled, and diethyl ether was added. The resultingprecipitate was filtered and washed with diethyl ether, and the solidwas dried in vacuo to provide 4-(4-bromoisoquinolin-1-ylamino)phenolhydrochloride as a purple solid.

EXAMPLE 27

Synthesis of 4-(4-phenylisoquinolin-1-ylamino)phenol

To a solution of 4-(4-bromoisoquinolin-1-ylamino)phenol (578 mg, 1834μmol), phenylboronic acid (335 mg, 2751 μmol), and tetrakis(triphenylphosphine) palladium (0) (212 mg, 183 μmol) in toluene (10480μl, 1834 μmol) and ethanol (2620 μl, 1834 μmol) was added sodiumcarbonate (6281 μl, 12563 μmol) in water (2M). The reaction mixture washeated to 100° C. overnight. The reaction progress was monitored byLCMS, which showed conversion to4-(4-phenylisoquinolin-1-ylamino)phenol. The product was purified bysilica gel chromatography (eluent: hexanes:EtOAc 0-50%) to yield4-(4-phenylisoquinolin-1-ylamino)phenol.

EXAMPLE 28 Synthesis ofN-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)-4-(chloro)phthalazin-1-amine

In a 150 mL pressure tube was dissolved4-(7-methoxy-1,5-naphthyridin-4-yloxy)benzenamine (6.1 g, 23 mmol) intBuOH (75 mL). To this solution was added 1,4-dichlorophthalazine (10.0g, 50 mmol) and the mixture was placed in pre-heated oil bath at 100° C.A thick clay formed at the bottom of the tube after 20 minutes. LCMS onsolid at the bottom of the tube showed mainly desired product with traceamounts of starting material. This solid material was dissolved andtransferred to a flask using hot 90/10/1 (CH₂Cl₂/MeOH/ammoniumhydroxide), and evaporated to dryness. The crude was dissolved in CH₂Cl₂and washed with sat. sodium bicarbonate. The organic layer was separatedand dried over sodium sulfate, and then concentrated. The mixture wasthen dissolved in approx. 30/70 MeOH/CH₂Cl₂, silica was added and themix was concentrated to dryness. This silica pre-absorbed material waspurified using 0 to 100% 90/10/1 (CH₂Cl₂/MeOH/ammonium hydroxide) toafford the title compound. MS Found: [M+H]=430.0. Calc'd forC₂₃H₁₆ClN₅O₂: 429.9.

EXAMPLE 29 Method A1 Synthesis of3-(4-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenylamino)phthalazin-1-yl)benzonitrile

In a nitrogen purged sealed tube, 1,4-dioxane (1.4 mL) was added and thetube was purged with nitrogen for 5 min and sealed. 3-Cyanophenylboronicacid (0.056 g, 0.384 mmol),4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine(0.150 g, 0.349 mmol), and 2.0 M sodium carbonate (0.349 mL, 0.698 mmol)were added to the tube, followed by1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.013 g,0.017 mmol). The tube was purged with nitrogen, sealed, and the mixturewas heated to 100° C. for 17 h. The mixture was allowed to cool to RTand was concentrated in vacuo. The crude material was purified by silicagel chromatography using 0-100% CH₂Cl₂:MeOH(90:10)/CH₂Cl₂. The remainingimpurities were removed by diluting the crude with methanol causing alight yellow solid to precipitate, which were filtered and air dried toyield3-(4-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenylamino)phthalazin-1-yl)benzonitrile.MS [M+H]=497.0; Calc'd 496.5 for C₃₀H₂₀N₆O₂.

EXAMPLE 30 Method A2 Synthesis ofN-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)-4-(1-methyl-1H-imidazol-2-yl)phthalazin-1-amine

In a nitrogen purged sealed tube was added 1,4-dioxane (1.35 mL), andthe solution was purged with nitrogen for 5 minutes, then sealed.1-Methyl-2-(tributylstannyl)-1H-imidazole (0.311 g, 0.837 mmol),4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine(0.120 g, 0.279 mmol) were added to the tube, which was then purged withnitrogen and sealed. To the tube was added1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.102 mg,0.140 mmol), and the tube was purged with nitrogen, sealed, and heatedto 100° C., while stirring the reaction for 17 hours. The reaction wascooled to RT, and concentrated. The concentrate was purified usingreverse phase chromatography, the product fractions were concentrated,extracted into DCM, washed once with sodium carbonate and once withwater, upon which the title compound precipiated. The solids werefiltered, washed with water, air dried to yieldN-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)-4-(1-methyl-1H-imidazol-2-yl)phthalazin-1-amine(0.039 g) as light yellow solid. MS [M+H]=476.0; Calc'd 475.5 forC₂₇H₂₁N₇O₂.

EXAMPLE 31 Method A3 Synthesis of4(3,3-dimethylbut-1-ynyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine

A resealable pressure bottle, purged with argon, was charged with4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine(120 mg, 0.28 mmol), bis(triphenylphosphine)palladium(ii) chloride (24mg, 0.03 mmol), copper(I) iodide (6.4 mg, 0.03 mmol),3,3-dimethyl-1-butyne (86 μl, 0.70 mmol), and ACN (2.8 mL, 0.1 M). Tothe mixture was added TEA (0.785 mL, 5.6 mmol). The reaction vessel wassealed and the mixture was heated to 90° C. for 16 h. The reactionmixture was cooled to RT, diluted with DCM and filtered over Celite. Thefiltrate was concentrated under reduced pressure to give a brownresidue, which was purified by Gilson HPLC {5-65% (0.1% TFA in CH₃CN) inH₂O over 20 min}. The product-containing fractions were combined,basified by addition of aq. NaHCO₃ and extracted with DCM. The organicportion was dried with Na₂SO₄, filtered, and concentrated to afford pure4-(3,3-dimethylbut-1-ynyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amineMS [M+H]=476.1 Calc'd for C₂₉H₂₅N₅O₂: 475.5.

EXAMPLE 32 Method B1

Synthesis of4-(azepan-1-yl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine

A pyrex reaction tube was charged with4-(7-methoxy-1,5-naphthyridin-4-yloxy)benzenamine (128 mg, 0.478 mmol),1-(azepan-1-yl)-4-chlorophthalazine (125 mg, 0.478 mmol), TFA (0.029 ml,0.382 mmol) and 2.4 mL of 2-BuOH. The tube was sealed and the reactionmixture was heated at 100° C. for 1.5 h. Upon cooling, EtOAc was added,and the resulting precipitate was filtered and washed with EtOAc. Thesolid was dissolved in 90/10/1 CH₂Cl₂/MeOH/NH₄OH and purified by silicagel chromatography with 90/10/1 CH₂Cl₂/MeOH/NH₄OH. The material wasfurther purified by reverse phase chromatography (Gilson, 5-95% ACN over15 min) to provide4-(azepan-1-yl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amineas a tan solid. MS m/z=493 [M+H]⁺. Calc'd for C₂₉H₂₈N₆O₂: 492.57.

EXAMPLE 33 Method B2 Synthesis ofN-(4-(1,5-naphthyridin-4-ylthio)phenyl)-4-(4-chlorophenyl)phthalazin-1-amine

1-Chloro-4-(4-chlorophenyl)phthalazine (30 mg, 109 μmol),p-toluenesulfonic acid monohydrate (10 mg, 55 μmol) and4-(1,5-naphthyridin-4-ylthio)benzenamine (33 mg, 131 μmol) were combinedin t-butanol in a sealed tube and the reaction mixture was stirred at100° C. for 2 h. The mixture was concentrated in vacuo and the crudematerial was purified by silica gel chromatography (0 to 100% 90/10/1CH₂Cl₂/MeOH/NH₄OH) in CH₂Cl₂. The material was further purified bysilica gel chromatography (0 to 100% EtOAc/hexane) to affordN-(4-(1,5-naphthyridin-4-ylthio)phenyl)-4-(4-chlorophenyl)phthalazin-1-amine.MS [M+H]=492; Calc'd 491.99 for C₂₈H₁₈ClN₅S.

EXAMPLE 34 Method B3 Synthesis of4-(4,5-dimethylthiophen-2-yl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine

In a nitrogen purged sealed tube,1-chloro-4-(4,5-dimethylthiophen-2-yl)phthalazine (0.040 g, 0.146 mmol)was dissolved in tert-butanol (1.00 mL).4-(7-Methoxy-1,5-naphthyridin-4-yloxy)benzenamine (0.039 g, 0.146 mmol)was added, and the reaction mixture in the tube was stirred at 100° C.for 3 h. The mixture was concentrated in vacuo, and the crude materialwas purified by silica gel chromatography using 0-100%CH₂Cl₂:MeOH(90:10)/CH₂Cl₂. Product-containing fractions wereconcentrated to yield4-(4,5-dimethylthiophen-2-yl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amineas light yellow solid. MS [N+H]=506.0; Calc'd 505.6 for C₂₉H₂₃N₅O₂S.

EXAMPLE 35 Method B4 Synthesis of4-ethyl-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-6-p-tolylpyridazin-3-amine

A pyrex reaction tube was charged withtris(dibenzylideneacetone)dipalladium (20 mg, 0.021 mmol),4-(7-methoxy-1,5-naphthyridin-4-ylthio)benzenamine (122 mg, 0.430 mmol),sodium tert-butoxide (99 mg, 1.031 mmol), S-Phos (35 mg, 0.086 mmol),and 3-chloro-4-ethyl-6-p-tolylpyridazine (100 mg, 0.430 mmol). Thereaction tube was purged with nitrogen. 1.3 mL of toluene was added, andthe tube was sealed. The reaction mixture was heated at 100° C. for 3 h.Upon cooling, the mixture was diluted with 5% iPrOH/EtOAc and washedwith water. The organic portion was dried with MgSO₄, filtered andconcentrated. The crude material was purified by silica gelchromatography (90/10/1 CH₂Cl₂/MeOH/NH₄OH) and reverse phasechromatography (Gilson, 10-95% CH₃CN over 15 min) to provide4-ethyl-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-6-p-tolylpyridazin-3-amineas a light yellow solid. MS m/z=480 [M+H]⁺. Calc'd for C₂₈H₂₅N₅OS:479.60.

EXAMPLE 36 Method B5)

Synthesis ofN⁵-(7-Methoxy-1,5-naphthyridin-4-yl)-N²-(4-phenylphthalazin-1-yl)pyrimidine-2,5-diamine

N⁵-(7-methoxy-1,5-naphthyridin-4-yl)pyrimidine-2,5-diamine (90 mg, 335μmol), 1-chloro-4-phenylphthalazine (97 mg, 403 μmol), THF (1677 μl, 335μmol), and LiHMDS (1006 μl, 1006 μmol) were added into a pressure tube.The mixture was stirred at RT for 10 min. A red solution was formed. Thetube was placed in a preheated oil bath at 100° C. After 1 h, LCMSshowed complete conversion of SM to product. The reaction was cooled tort. Hexane was added to induce the product to precipitate out of thereaction mixture. The resulting red solid was filtered with an aid ofhexane. LCMS confirmed that the solid was the product. The product waspurified by performing a column chromatography on silica gel using 60:40CH₂Cl₂:(90:10:1 CH₂Cl₂:MeOH:NH₄OH). Yellow solid was obtained. LCMSconfirmed product. HPLC showed 96% pure. ¹H NMR showed rotamers. Note:this cmpd was slightly soluble in DMSO at rt. MS Calcd for C₂₇H₂₀N₈O:[M]⁺=472. Found: [M+H]⁺=473.

EXAMPLE 37 Method C1

Synthesis ofN-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-methoxyphenyl)phthalazin-1-amine

A 5 mL microwave tube was charged with4-(4-(4-methoxyphenyl)phthalazin-1-ylamino)phenol and 3 equivalents ofcesium carbonate (342 mg, 1.048 mmol) in 1.8 mL of DMF. The mixture wasstirred at RT for 10 min. Following addition of8-chloro-3-methoxy-1,5-naphthyridine (88 mg, 0.454 mmol), the vessel wascapped and irradiated at 150° C. for 15 min in the microwave, at whichtime the reaction was determined complete by LC/MS. The mixture wascooled to ambient temperature and diluted with water. The solids werefiltered and washed with water. The solids were triturated withmethanol, filtered to remove remaining impurities, washed withadditional methanol and dried under vacuum to affordN-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-methoxyphenyl)phthalazin-1-amineas a light orange solid. MS [M+H]=502; Calc'd 501.54 for C₃₀H₂₅N₅O₃.

EXAMPLE 38 Method C2

Synthesis of4(4-tert-butylphenyl)N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine

In a nitrogen purged sealed tube, 8-chloro-3-methoxy-1,5-naphthyridine(0.053 g, 0.271 mmol) was dissolved in DMF (2.00 mL).4-(4-(4-Tert-butylphenyl)phthalazin-1-ylamino)phenol (0.100 g, 0.271mmol) and cesium carbonate (0.176 g, 0.541 mol) were added, and themixture in the tube was stirred at 90° C. for 17 h. Upon cooling to RT,the mixture was concentrated in vacuo, and purified by silica gelchromatography using 0-100% CH₂Cl₂:MeOH(90:10)/CH₂Cl₂ to yield4-(4-tert-butylphenyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amineas off-white solid. MS [M+H]=528.1; Calc'd 527.6 for C₃₃H₂₉N₅O₂.

EXAMPLE 39 Method C3

Synthesis ofN-(4-(3-fluoro-7-methoxyquinolin-4-yloxy)phenyl)-4-(4-(trifluoromethyl)phenyl)phthalazin-1-amine

Racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (84 mg, 210 μmol),4-chloro-3-fluoro-7-methoxyquinoline (67 mg, 315 μmol),4-(4-(4-(trifluoromethyl)phenyl)phthalazin-1-ylamino)phenol (80 mg, 210μmol), cesium carbonate (137 mg, 420 μmol), and Pd₂ dba₃ (96 mg, 105μmol) were combined in a resealable tube, and the tube was purged withnitrogen. Toluene (1049 μl, 210 μmol) was added and the tube was sealedand heated to 100° C. overnight. Analysis by LCMS showed incompleteconversion to product. The reaction mixture was diluted with water andDCM, and the water layer was separated and extracted first with DCMfollowed by ethyl acetate. The combined organic extracts were dried overMgSO₄, filtered, and concentrated in vacuo. The dark residue was takenup in DCM and hexanes, and a precipitate formed. The solid was filteredand purified by preparative HPLC. The crude reaction mixture was takenup in minimal DMSO and methanol and purified on the Gilson {15-85% (0.1%TFA in CH₃CN) in H₂O over 20 min}. Clean product containing fractionswere combined and neutralized with saturated aqueous NaHCO₃ thenextracted with ethyl acetate, dried over MgSO₄, filtered andconcentrated in vacuo to affordN-(4-(3-fluoro-7-methoxyquinolin-4-yloxy)phenyl)-4-(4-(trifluoromethyl)phenyl)phthalazin-1-amine as a tan solid. Further purification was accomplishedby silica gel chromatography (90:10 CH₂Cl₂:MeOH).N-(4-(3-fluoro-7-methoxyquinolin-4-yloxy)phenyl)-4-(4-(trifluoromethyl)phenyl)phthalazin-1-amine was afforded as a tan solid. MS [M+H]=557.0. Calc'dfor C₁₉H₂₁N₅O: 556.15.

EXAMPLE 40 Method C4

Synthesis ofN¹-(7-methoxy-1,5-naphthyridin-4-yl)N⁴-(4-phenylphthalazin-1-yl)benzene-1,4-diamine

In a 20 mL sealed tube was dissolved8-chloro-3-methoxy-1,5-naphthyridine (70 mg, 360 μmol) in DMF (2.00 mL).To this was added N1-(4-phenylphthalazin-1-yl)benzene-1,4-diamine (124mg, 396 μmol) and the reaction mixture was stirred at 70° C. for 17 h.Upon cooling to RT, the mixture was dissolved in DMF and purified usingGilson reverse phase chromatography. The product fractions werecombined, concentrated and the resulting crude was extracted into DCM,washed 1× sodium carbonate, 1×H₂O, dried with Na₂SO₄, filtered throughfritted funnel, concentrated to yieldN1-(7-methoxy-1,5-naphthyridin-4-yl)-N4-(4-phenylphthalazin-1-yl)benzene-1,4-diamineas light yellow solid. MS [M+H]=471.0; Calc'd 470.5 for C₂₉H₂₂N₆O.

EXAMPLE 41 Method C5 Synthesis ofN-(6-(7-methoxy-1,5-naphthyridin-4-yloxy)pyridin-3-yl)-4-phenylphthalazin-1-amine

A pyrex reaction tube was charged with8-chloro-3-methoxy-1,5-naphthyridine (50 mg, 0.26 mmol),5-(4-phenylphthalazin-1-ylamino)pyridin-2-ol (80 mg, 0.26 mmol), cesiumcarbonate (249 mg, 0.76 mmol) and DMSO (2 mL). The tube was sealed andthe reaction mixture was heated to 130° C. After 3.5 h, an aliquot wasanalyzed by LCMS, and the desired product was determined to be the majorpeak. The reaction mixture was diluted with DMSO and purified by GilsonHPLC {5-65% (0.1% TFA in CH₃CN) in H₂O over 20 min}. Theproduct-containing fractions were combined, basified by addition of aq.NaHCO₃ and extracted with DCM. The organic portion was dried withNa₂SO₄, filtered, and concentrated to afford material that was furtherpurified by silica gel chromatography, 90/10/1 CH₂Cl₂/MeOH/NH₄OH. ThisprovidedN-(6-(7-methoxy-1,5-naphthyridin-4-yloxy)pyridin-3-yl)-4-phenylphthalazin-1-amineas pure material. MS [M+H]=473.0@1.48 minutes. Calc'd for C₂₈H₂₀N₆O₂:472.5.

EXAMPLE 42 Method D1a

Synthesis ofN-(4-(7-Morpholinoquinolin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine

The title compound was prepared according to a method described in Ali,M. H.; Buchwald, S. L. J. Org. Chem. 2001, 66, 2560. Pd₂(dba)₃(21 mg, 23μmol), DavePhos (18 mg, 46 μmol), and sodium tert-butoxide (110 mg, 1141μmol) were added into a screw-capped tube equipped with a stir bar. Thetube was purged with argon.N-(4-(7-Bromoquinolin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine (237mg, 456 μmol) was added to the purged tube, followed by morpholine (159μl, 1825 μmol), 1,4-dioxane (2074 μl, 456 μmol), and tert-butanol (1037μl, 456 μmol). The tube was sealed and heated to 100° C. in an oil bathfor 1 h. The reaction was cooled to rt, and 22 mg of Pd₂(dba)₃, 20 mg ofDavePhos, and 80 mg of NaOt-Bu were added. The tube was resealed andplaced in a preheated oil bath at 100° C. After another 3.5 h, LCMSshowed mainly product at 1.434 min as [M+H]⁺=526. The mixture was passedthrough a pad of celite with an aid of CH₂Cl₂. The filtrate wasconcentrated. The product was purified by column chromatography onsilica gel eluting with 70:30 to obtain top spot, then washing with60:40 CH₂Cl₂:(90:10:1 CH₂Cl₂:MeOH:NOH) to collect the product. Fractionscontaining the product were concentrated. A yellow solid was obtainedand dried in the vacuum oven. The yellow solid was further purified byRPLC on the acidic Gilson workstation. Fractions containing the productwere diluted with CH₂Cl₂ and neutralized with sat. NaHCO₃. The organiclayer was separated, dried over MgSO₄, filtered, and concentrated.Yellow solid was obtained. HPLC showed 100% pure. LCMS confirmedproduct. MS Calcd for C₃₃H₂₇N₅O₂: [M]⁺=525. Found: [M+H]⁺=526.

EXAMPLE 43 Method D1b

Synthesis ofN-(4-(4-(4-Phenylphthalazin-1-ylamino)phenoxy)quinolin-6-yl)acetamide

The title compound was prepared according to a method described inGarnier, E.; Andoux, J.; Pasquinet, E.; Suzenet, F.; Poullain, D.;Lebret, B.; Guillaumet, G. J. Org. Chem. 2004, 69, 7809. Xantphos (22mg, 39 μmol) and 1,4-Dioxane (963 μl, 193 μmol) were added into a sealedtube. The tube was purged with argon, Palladium(II) acetate (4 mg, 19μmol) was added, and the mixture was stirred under argon for 10 min. Ina separate sealed tube,N-(4-(6-bromoquinolin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine (100mg, 193 μmol), acetamide (57 mg, 963 μmol), potassium carbonate (798 mg,5776 μmol), and 1,4-dioxane (963 μl, 193 μmol) were added. Then thePd(OAc)₂/Xantphos solution from the first tube was added with viasyringe to the second tube. The resulting mixture was heated to 110° C.under an argon atmosphere with vigorous stirring until the halidedisappeared. After 16 h, LCMS showed product at 1.324 as [M+H]⁺=498. Thereaction was cooled to rt, quenched with water, extracted with CH₂Cl₂.The organic portions were combined, washed with brine, dried over MgSO₄,filtered, and concentrated. The product was purified by RPLC on theacidic Gilson workstation. To provideN-(4-(4-(4-phenylphthalazin-1-ylamino)phenoxy)quinolin-6-yl)acetamide.MS Calcd for C₃₁H₂₃N₅O₂: [M]⁺=497. Found: [M+H]⁺=498.

EXAMPLE 44 Method D2

Synthesis of8(4-(4-phenylphthalazin-1-ylamino)phenoxy)-1,5-naphthyridine-3-carbonitrile

A pyrex reaction tube was charged withN-(4-(7-bromo-1,5-naphthyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine(200 mg, 0.384 mmol), ZnCN₂(54.2 mg, 0.461 mmol), and palladium tetrakis(22.2 mg, 0.019 mmol) and was purged with nitrogen. 1.2 mL of DMF wasadded and the tube was purged with nitrogen for several minutes and thensealed. The reaction mixture was heated at 85° C. for 4 h. Upon coolingthe mixture was poured into water, and the solids were filtered andwashed with water. The crude material was dissolved in a mixture of MeOHand DMSO and purified by reverse phase chromatography (Gilson, 10-95%ACN over 15 min) to provide8-(4-(4-phenylphthalazin-1-ylamino)phenoxy)-1,5-naphthyridine-3-carbonitrileas a light yellow solid. MS m/z=467 [M+H]⁺. Calc'd for C₂₉H₁₈N₆O:466.49.

EXAMPLE 45 Method D3

Synthesis ofN-(4-(6-(1-Methyl-1H-pyrazol-4-yl)quinolin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine

A sealed tube was charged withN-(4-(6-bromoquinolin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine (110mg, 212 μmol), sodium carbonate (2.0 M aqueous) (424 μl, 847 μmol), and1,4-dioxane (1059 μl, 212 μmol) under an argon atmosphere. Afterstirring for 5 min,1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (75mg, 360 μmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladiumdichloride (15 mg, 21 μmol) were added, and the tube was sealed andheated to 100° C. After 2 h, LCMS showed mainly product. The product wasextracted with CH₂Cl₂, washed with brine, dried over MgSO₄, filtered,and concentrated. The crude residue was purified by RPLC on the acidicGilson workstation. Fractions containing the product were diluted withCH₂Cl₂ and neutralized with sat. NaHCO₃. The organic layer wasseparated, dried over MgSO₄, filtered, and concentrated. Yellow solidwas obtained.N-(4-(6-(1-methyl-1H-pyrazol-4-yl)quinolin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine.MS Calcd for C₃₃H₂₄N₆O: [M]⁺=520. Found: [M+H]⁺=521.

EXAMPLE 46

Synthesis of7-(4(4-phenylphthalazin-1-ylamino)phenoxy)thieno[3,2-b]pyridine-2-carboxamide

A 5 ml microwave tube was charged with7-(4-aminophenoxy)thieno[3,2-b]pyridine-2-carboxamide (85 mg, 0.300mmol) and 1-chloro-4-phenylphthalazine (60 mg, 0.250 mmol) in 2.0 ml oftert-butanol. The vessel was capped and irradiated at 140° C. for 15minutes in the microwave. Analysis of an aliquot of the crude mixture byLCMS showed remaining starting material and approximately 20% conversionto desired product. Irradiated at 150° C. for an additional 20 minutes,at which time reaction was deemed complete by LCMS analysis. Cooled toambient temperature and diluted reaction mixture with methanol. Filteredsolids, washed with additional methanol and concentrated in vacuo toafford7-(4-(4-phenylphthalazin-1-ylamino)phenoxy)thieno[3,2-b]pyridine-2-carboxamide.MS m/z=490 [M+H]⁺. Calc'd for C₂₈H₁₉N₅O₂S: 489.55.

EXAMPLE 47

Synthesis of4-(4-(4(5-fluoro-2-methoxyphenyl)phthalazin-1-ylamino)phenoxy)quinoline-7-carboxamide

A sealed tube was charged with4-(4-(4-(5-fluoro-2-methoxyphenyl)phthalazin-1-ylamino)phenoxy)quinoline-7-carbonitrile(150 mg, 0.529 mmol) in neat concentrated sulfuric acid (3 mL). The tubewas sealed and placed in a preheated oil bath at 80° C. for 1 h, atwhich point the reaction was determined complete by LCMS. The reactionwas cooled to RT and added drop-wise to sat. sodium bicarbonate in anice bath. Neutralized the mixture with 2N NaOH to a pH of 7 andextracted with ethyl acetate (3×). Organic layers were dried overmagnesium sulfate, filtered and concentrated. The crude was purified viasilica gel chromatography using a slow gradient of 90:10:1(DCM:methanol:ammonium hydroxide) in DCM. Fractions contained thedesired material were pooled and concentrated in vacuo to afford4-(4-(4-(5-fluoro-2-methoxyphenyl)phthalazin-1-ylamino)phenoxy)quinoline-7-carboxamideas a tan solid. MS m/z=532 [M+H]⁺. Calc'd for C₃₁H₂₂FN₅O₃: 531.54.

EXAMPLE 48

Synthesis of4-(4-(4-ethyl-6-phenylpyridazin-3-ylamino)phenoxy)quinoline-7-carboxamide

A microwave reaction vial was charged with4-chloroquinoline-7-carbonitrile (97.1 mg, 0.515 mmol),4-(4-ethyl-6-phenylpyridazin-3-ylamino)phenol (150 mg, 0.515 mmol),cesium carbonate (252 mg, 0.772 mmol) and 2.6 mL of DMSO. The vial wassealed, and the reaction mixture was irradiated in the microwave at 150°C. for 15 min. Upon cooling the mixture was poured into water and theresulting solids were filtered and washed with water. The crude solidswere dissolved in 90/10/1 CH₂Cl₂/MeOH/NH₄OH and purified by silica gelchromatography, 5-100% 90/10/1: CH₂Cl₂ over 25 min which provided4-(4-(4-ethyl-6-phenylpyridazin-3-ylamino)phenoxy)quinoline-7-carboxamideas a tan solid. MS m/z=462 [M+H]⁺. Calc'd for C₂₈H₂₃N₃O₂: 461.52.

EXAMPLE 49

Synthesis of 3-chloro-4-isopropyl-6-phenylpyridazine

A RBF was charged with 3-chloro-4-ethyl-6-phenylpyridazine (250 mg,1.143 mmol) and 5.7 mL of THF, and the mixture was cooled to −78° C.under nitrogen. Lithium diisopropylamide, 2.0 M solution inheptane/tetrahydrofuran/ethylbenzene (0.686 mL, 1.372 mmol) was added,and the mixture was stirred for 5 min at −78° C., followed by 1 h atroom temperature. The mixture was cooled back down to −78° C., andmethyl iodide (195 mg, 1.372 mmol) that had been passed through a plugof basic alumina prior to use was added dropwise. The reaction wasstirred at this temperature for 5 min, followed by RT for 0.5 h. Afterquenching with water, the solution was diluted with CH₂Cl₂ and thelayers were separated. The aqueous portion was extracted with additionalCH₂Cl₂ and the combined organics were dried with MgSO₄, filtered andconcentrated. The crude material was purified by silica gelchromatography (CH₂Cl₂— 10% MeOH/CH₂Cl₂) to provide3-chloro-4-isopropyl-6-phenylpyridazine as a colorless oil, whichcrystallized upon standing. MS m/z=233 [M+H]⁺. Calc'd for C₁₃H₁₃ClN₂:232.71.

EXAMPLE 50

Synthesis ofN1-(7-methoxy-1,5-naphthyridin-4-yl)-N-1-methyl-N4-(4-phenylphthalazin-1-yl)benzene-1,4-diamineStep 1: 7-methoxy-N-methyl-N-(4-nitrophenyl)-1,5-naphthyridin-4-amine

To a resealable pressure vessel was added n-methyl-4-nitroaniline (0.911ml, 7.19 mmol), pyridinium p-toluenesulfonate (1.81 g, 7.19 mmol),8-chloro-3-methoxy-1,5-naphthyridine (1.000 g, 5.14 mmol), and n-BuOH(15 mL). The vessel was sealed and heated to 100° C. After 4 h, themixture was cooled to RT, diluted with 1 N NaOH, and extracted withEtOAc. The organic fraction was dried with Na₂SO₄, concentrated invacuo, and purified by silica gel chromatography using 50-100%Hexanes:EtOAc to afford7-methoxy-N-methyl-N-(4-nitrophenyl)-1,5-naphthyridin-4-amine as ayellow solid. MH+=311.2@1.51 min.

Step 2:N1-(7-methoxy-1,5-naphthyridin-4-yl)-N1-methylbenzene-1,4-diamine

To a mixture of7-methoxy-N-methyl-N-(4-nitrophenyl)-1,5-naphthyridin-4-amine (0.233 g,0.751 mmol) in MeOH (10 mL) at RT was added a suspension of 10%palladium on carbon (0.0799 g, 0.751 mmol) in EtOAc (10 mL). The mixturewas exposed to an atmosphere of hydrogen (balloon). After 4 h, themixture was filtered over celite and concentrated in vacuo. The crudeyellow foam,N1-(7-methoxy-1,5-naphthyridin-4-yl)-NI-methylbenzene-1,4-diamine, wasadvanced without further purification. MH+=281.2@1.21 min.

Step 3:N1-(7-methox-10,5-naphthyridin-4-yl)-N1-methyl-N4-(4-phenylphthalazin-1-yl)benzene-1,4-diamine

A mixture ofN1-(7-methoxy-1,5-naphthyridin-4-yl)-N1-methylbenzene-1,4-diamine (0.061g, 0.22 mmol) and 1-chloro-4-phenylphthalazine (0.052 g, 0.22 mmol) washeated at 100° C. for 48 h. The solvent was removed in vacuo and theresidue was purified by silica gel chromatography using 1-10%MeOH:CH₂Cl₂ containing 1% NH₄OH to affordN1-(7-methoxy-1,5-naphthyridin-4-yl)-N1-methyl-N4-(4-phenylphthalazin-1-yl)benzene-1,4-diamineas a yellow solid.

EXAMPLE 51

Synthesis of 4(5,6,7,8-tetrahydro-1,5-naphthyridin-4-yloxy)benzenamine

To a solution of 4-(7-bromo-1,5-naphthyridin-4-yloxy)benzenamine (0.150g, 0.474 mmol) in MeOH (7 mL) at RT was added a suspension of 10%palladium on carbon (0.0505 g, 0.474 mmol) in EtOAc (2 mL). The mixturewas subjected to an atmosphere of hydrogen (balloon) and stirredovernight. After 18 hrs, the mixture was filtered over celite andconcentrated in vacuo. The resulting tan foam, crude4-(5,6,7,8-tetrahydro-1,5-naphthyridin-4-yloxy)benzenamine, was advancedwithout further purification. MH+=242.2@0.49 min

EXAMPLE 52 Synthesis ofN-(4-(1,5-naphthyridin-4-yloxy)phenyl-4-phenylphthalazin-1-amine

To a mixture of tetrakis(triphenylphosphine)palladium (9 mg, 0.0079mmol) and sodium methoxide (9 mg, 0.16 mmol) was added a solution ofN-(4-(7-bromo-1,5-naphthyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine(0.041 g, 0.079 mmol) in DMF (2 mL). The mixture was heated to 100° C.in an Argon purged, resealable tube. After 3 hrs, the solvent wasremoved in vacuo and the residue was purified by silica gelchromatography using 1-10% MeOH:CH₂Cl₂ containing 1% NH₄OH to affordN-(4-(1,5-naphthyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine as atan solid. MH+=442.1@1.51 min.

EXAMPLE 53

Synthesis ofN-(4-((7-methoxyquinolin-4-yl)methyl)phenyl)-4-phenylphthalazin-1-amineStep 1: 7-Methoxy-4-(phenylthio)quinoline

A resealable tube under N₂ was charged with 4-chloro-7-methoxyquinoline(1.00 g, 5.16 mmol), thiophenol (0.528 ml, 5.16 mmol), cesium carbonate(2.52 g, 7.75 mmol) and DMSO (5 mL). The mixture was heated at 100° C.for 2 hrs. The crude reaction mixture was directly purified by silicagel chromatography using 0-10% CH₂Cl₂:MeOH to afford7-methoxy-4-(phenylthio)quinoline as a off-white solid. MH+=268.0.

Step 2: 7-Methox-4-(phenylsulfinyl)quinoline

To 7-methoxy-4-(phenylthio)quinoline (1.38 g, 5.16 mmol) in CH₂Cl₂(50mL) at −78° C. was added m-CPBA (77%) (1.25 g, 7.23 mmol) portionwise.The mixture was allowed to slowly warm to RT (3 hrs). The reactionmixture was diluted with CH₂Cl₂ then neutralized with NaHCO₃(sat.). Theaqueous phase was extracted three times with CH₂Cl₂ then the organiclayer was dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude mixture was purified by silica gel chromatography using 0-10%CH₂Cl₂:MeOH to afford 7-methoxy-4-(phenylsulfinyl)quinoline (1.37 g, 94%yield) as a off-white foam. MH+=284.0.

Step 3: (7-Methoxyquinolin-4-yl)(4-nitrophenyl)methanol

To a solution of 7-methoxy-4-(phenylsulfinyl)quinoline (0.232 g, 0.819mmol) in THF (6 mL) at −78° C. was added phenylmagnesium chloride (2.0 Min THF) (0.819 ml, 1.64 mmol). After 5 min, the solution was warmed toRT for 15 minutes. The solution was then cooled to −78° C. and4-nitrobenzaldehyde (0.371 g, 2.46 mmol) was added in one portion. After5 min, the solution was warmed to RT. After 1 hr at RT, the reaction wasquenched with saturated NH₄Cl. The mixture was diluted with CH₂Cl₂ andwashed with water and brine. The organic fraction was dried with Na₂SO₄and concentrated in vacuo. The yellow residue was purified by silica gelchromatography using 20-100% Hexanes:EtOAc to afford(7-methoxyquinolin-4-yl)(4-nitrophenyl)methanol as a white solid.MH+=311.2@1.44 min

Step 4: 4-((7-Methoxyquinolin-4-yl)methyl)benzenamine

A mixture of (7-methoxyquinolin-4-yl)(4-nitrophenyl)methanol (0.187 g,0.603 mmol) and tin(II) chloride dihydrate (0.823 g, 3.62 mmol) in MeOH(10 mL) was heated to 60° C. After 1 hr, an additional 5 eq of tin(II)chloride dihydrate was added. After 3 hrs, the mixture was concentratedin vacuo and diluted with EtOAc and water. Saturated NaHCO₃ was addeduntil the aqueous layer was basic. The resulting suspension was filteredand the solids washed with EtOAc. The organic fraction was washed withwater and brine. After drying with Na₂SO₄ and concentrating in vacuo,the crude yellow solid, 4-((7-methoxyquinolin-4-yl)methyl)benzenaminewas advanced without further purification. MH+=265.1@0.99 min.

Step 5:N-(4-((7-Methoxyquinolin-4-yl)methyl)phenyl)-4-phenylphthalazin-1-amine

A mixture of 1-chloro-4-phenylphthalazine (0.082 g, 0.34 mmol) and4-((7-methoxyquinolin-4-yl)methyl)benzenamine (0.090 g, 0.34 mmol) intBuOH (2.5 mL) was heated to 105° C. in a resealable tube. After 3 hrs,the mixture was cooled to RT, diluted with CH₂Cl₂ and washed withsaturated NaHCO₃ and brine. The organic fraction was dried with Na₂SO₄,concentrated in vacuo, and purified by silica gel chromatography using50-100% Hexanes:EtOAc to affordN-(4-((7-methoxyquinolin-4-yl)methyl)phenyl)-4-phenylphthalazin-1-amineas a light yellow solid. MH+=469.2@1.47 min

EXAMPLE 54

Synthesis ofN-(5-(7-methoxy-1,5-naphthyridin-4-yloxy)pyridin-2-yl)-4-phenylphthalazin-1-amineStep 1. N-(2,4-dimethoxybenzyl)-4-phenylphthalazin-1-amine

In a nitrogen purged 75 mL sealed tube, dissolved2,4-dimethoxybenzylamine hydrochloride (2.54 g, 12.5 mmol), cesiumcarbonate (4.06 g, 12.5 mmol) in tBuOH (15 mL). Added1-chloro-4-phenylphthalazine (2.0 g, 8.31 mmol)and the tube was stirredat 100° C. for 17 h. The tube was cooled to RT, and the mixture wasconcentrated in vacuo. Dissolved the crude material in DCM, and filteredthe solution to remove cesium carbonate. Performed silica gelchromatography using 0-100% EtOAc/Hex and concentrated to yieldN-(2,4-dimethoxybenzyl)-4-phenylphthalazin-1-amine as orange oil. MS[M+H]=372; Calc'd 371.4 for C₂₃H₂₁N₃O₂.

Step 2. 4-phenylphthalazin-1-amine

In a 150 mL sealed tube, dissolvedN-(2,4-dimethoxybenzyl)-4-phenylphthalazin-1-amine (3.00 g, 8.1 mmol) inacetic acid (40 mL). Hydrobromic acid (48% aqueous) (2.6 mL, 24 mmol)was added and the tube was stirred at 90° C. for 3 h. The solution wascooled to RT, and slowly poured into water, which caused a pink solid tocrash out. The solid was filtered and rinsed with water. The productcontaining filtrate was slowly poured into saturated sodium carbonate.The aqueous phase was extracted with DCM, washed twice with water, driedwith Na₂SO₄, filtered through fritted funnel, and concentrated to yield4-phenylphthalazin-1-amine as light yellow solid. MS [M+H]=222; Calc'd221.3 for C₁₄H₁₁N₃.

Step 3.N-(5-(7-methoxy-1,5-naphthyridin-4-yloxyy)pridin-2-yl)-4-phenylphthalazin-1-amine

In a nitrogen purged sealed tube was added toluene (1.5 mL), purged thesolvent with nitrogen for 5 minutes and sealed the tube. To the tube wasadded 8-(6-bromopyridin-3-yloxy)-3-methoxy-1,5-naphthyridine (0.100 g,0.301 mmol), 4-phenylphthalazin-1-amine (0.080 g, 0.361 mmol), sodiumtert-butoxide (0.072 g, 0.753 mmol), and the tube was again purged withnitrogen and sealed. Added tBu X-phos (0.013 g, 0.030 mmol),tris(dibenzylideneacetone)dipalladium (o) (0.007 g, 0.008 mmol), purgedthe reaction with nitrogen, sealed, heated the tube to 100° C., stirringfor 24 h. The reaction was cooled to RT, filtered through pad of silicagel, washed with 100% CH₂Cl₂:MeOH(90:110)/CH₂Cl₂ and concentrated. Thecrude was purified using reverse phase chromatography, extracted theconcentrated product fractions into DCM, washed the organic layer 1×with sodium carbonate, 1×H₂O, dried with Na2SO4, filtered solutionthrough fritted funnel, and concentrated the filtrate to affordN-(5-(7-methoxy-1,5-naphthyridin-4-yloxy)pyridin-2-yl)-4-phenylphthalazin-1-amineas light yellow solid. MS [M+H]=473; Calc'd 472.5 for C₂₈H₂₀N₆O₂.

EXAMPLE 55

Synthesis of4-(4-ethynylphenyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amineStep 1.N-(4-(7-Methox-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-(2-(triethylsilyl)ethynyl)phenyl)phthalazin-1-amine

In an argon purged sealed pressure vessel was added4-(4-chlorophenyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine(0.120 g, 0.237 mmol), cesium carbonate (0.201 g, 0.617 mmol), X-phos(0.017 g, 0.0356 mmol), dichloropalladium bisacetonitrile (0.003 mg,0.011 mmol), and acetonitrile (0.50 mL). Starting material was notsoluble in acetonitrile, so added 0.5 mL 1,4 dioxane. Purged thereaction with argon, then added (triethylsilyl)acetylene (0.055 mL,0.308 mmol), and again purged with vessel with argon, sealed, heated itto 90° C. The reaction was stirred for 1 h. Reaction complete by LC/MS.The reaction was cooled to RT, passed through pad of silica, washed with100% CH₂Cl₂:MeOH(90:10)/CH₂Cl₂ and the organics were concentrated. Thecrude material was purified by silica gel chromatography eluting with0-100% CH₂Cl₂:MeOH(90:10)/CH₂Cl₂. The product fractions wereconcentrated to yieldN-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-(2-(triethylsilyl)ethynyl)phenyl)phthalazin-1-amineas light yellow solid. MS [M+H]=610.2; Calc'd 609.8 for C₃₇H₃₅N₅O₂Si.

Step 2.4-(4-Ethypylphenyl)-N-(4-(7-methoxn-1,5-naphtpyridin-4-yloxy)phenyl)phthalazin-1-amine

In a nitrogen purged sealed tube was dissolvedN-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-(2-(triethylsilyl)ethynyl)phenyl)phthalazin-1-amine(0.100 g, 0.164 mmol) in MeOH (2.00 mL). Potassium carbonate (0.068 g,0.492 mmol) was added and the reaction was stirred at 20° C. for 24 hand then concentrated. The crude was extracted into DCM, washed 1× withwater, 1× with brine, dried over Na₂SO₄, filtered through frittedfunnel, concentrated. The resulting crude material was purified bysilica gel chromatography eluting with 0-100% CH₂Cl₂:MeOH(90:10)/CH₂Cl₂.The product fractions were concentrated to afford4-(4-ethynylphenyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amineas light yellow solid. MS [M+H]=496; Calc'd 495.5 for C₃₁H₂₁N₅O₂.

EXAMPLE 56

Synthesis of(6-(4-(4-(6,7-Dimethoxyquinolin-4-yloxy)phenylamino)phthalazin-1-yl)pyridin-2-yl)methanol

(6-(4-(4-(6,7-dimethoxyquinolin-4-yloxy)phenylamino)phthalazin-1-yl)pyridin-2-yl)methylacetate (45 mg, 78 mmol) was saponified in 0.5 mL of THF:MeOH:H₂O(3:1:1) in a screw-capped tube. Lithium hydroxide hydrate (26 mg, 620μmol) was added. After 1 h at rt, LCMS showed mainly product at 1.237min as [M+H]⁺=532. The product was extracted with CH₂Cl₂, washed withbrine, dried over MgSO₄, filtered, and concentrated. The product waspurified by performing column chromatography on silica gel using 40:60CH₂Cl₂:(90:10:1 CH₂Cl₂:MeOH:NH₄OH). Yellow glass was obtained and driedin the vacuum oven overnight. Yellow solid was obtained. LCMS confirmedproduct(6-(4-(4-(6,7-dimethoxyquinolin-4-yloxy)phenylamino)phthalazin-1-yl)pyridin-2-yl)methanol.MS Calcd for C₃₁H₂₅N₅O₄: [M]⁺=531. Found: [M+H]⁺=532.

EXAMPLE 57

Synthesis of N⁵-(7-Methoxyquinolin-4-yl)pyrimidine-2,5-diamine Step 1:N-(5-(7-Methoxyquinolin-4-ylamino)pyrimidin-2-yl)benzamide

In a screw cap test tube were dissolved8-chloro-3-methoxy-1,5-naphthyridine (281 mg, 1443 mmol),N-(5-aminopyrimidin-2-yl)benzamide (281 mg, 1312 μmol) and pyridiniump-toluenesulfonate (494 mg, 1968 mmol) in butan-2-ol (2623 μl, 1312μmol) then heated at 100° C. The reaction turned black in a minute.After 1 h, the reaction mixture showed full conversion to productaccording to LCMS. The reaction mixture was diluted with CH₂Cl₂,neutralized with sat. NaHCO₃. An emulsion was formed but the two layerseventually separated. The aqueous phase was extracted 3 times withCH₂Cl₂, washed with brine, dried over MgSO₄, filtered and evaporatedunder reduce pressure to give a tan solid. The solid was triturated withhexane, filtered, and dried under vacuo. Brown solid was collected. LCMSconfirmed the presence of the product,N-(5-(7-methoxy-1,5-naphthyridin-4-ylamino)pyrimidin-2-yl)benzamide. MSCalcd for C₂₀H₁₆N₆O₂: [M]⁺=372. Found: [M+H]⁺=373.

Step 2: N⁵-(7-Methoxyquinolin-4-yl)pyrimidine-2,5-diamine

In 25 mL sealed tube,N-(5-(7-methoxyquinolin-4-ylamino)pyrimidin-2-yl)benzamide (400 mg, 1077μmol) was added into 6 ml of MeOH followed by addition of 2 mL of HCl(conc.). The reaction was heated at 80° C. After 1.5 h the reactionmixture based on LCMS showed full conversion to desired product[M+H]⁺+1=269 @ 0.8 min—protonated form. The reaction was cooled to 0°C., 50 mL of CH₂Cl₂ was added, and the mixture was neutralized with 6NNaOH. Solid precipitated out of the solution in the aqueous layer. Thewhole mixture was concentrated under reduced pressure. The solid wasfiltered off with an aid of water to yield a sticky solid. The solid wastransferred into a flask with an aid of MeOH. The solvent was evaporatedunder reduced pressure to affordN5-(7-methoxyquinolin-4-yl)pyrimidine-2,5-diamine as a gray solid.

EXAMPLE 58

Synthesis of 4-(4-nitrobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a mixture of 3,4-dihydro-2H-benzo[b][1,4]oxazine (0.500 g, 3.70 mmol)and potassium carbonate (2.56 g, 18.5 mmol) in acetone (25 mL) was added1-(bromomethyl)-4-nitrobenzene (0.959 g, 4.44 mmol). The mixture washeated to reflux and stirred overnight. After 16 hrs the mixture wasconcentrated in vacuo, diluted with EtOAc, and washed with water andbrine. The organic fraction was dried over Na₂SO₄, concentrated invacuo, and the crude residue was purified by silica gel chromatographyusing 100% Hexanes to 30% Hexanes:EtOAc to afford4-(4-nitrobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine as an orange oil.MS found: M+H+=271.1.

EXAMPLE 59

Synthesis of 4-((2,3-dihydrobenzo[b][1,4]oxazin-4-yl)methyl)benzenamine

A mixture of 4-(4-nitrobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(0.432 g, 1.6 mmol) and tin(II) chloride dihydrate (1.8 g, 8.0 mmol) inMeOH (10 mL) was heated to 50° C. After 3 hrs the mixture wasconcentrated in vacuo and the residue taken up in EtOAc. SaturatedNaHCO₃ was added and the mixture was filtered. The filtrate was washedwith brine, dried with Na₂SO₄, concentrated in vacuo, and purified bysilica gel chromatography using 20-100% Hexanes:EtOAc to afford4-((2,3-dihydrobenzo[b][1,4]oxazin-4-yl)methyl)benzenamine as an orangeoil. MS found: M+H+=241.1.

EXAMPLE 60

Synthesis of 7-methoxy-4(phenylsulfinyl)quinoline

To a mixture of 7-methoxy-4-(phenylthio)quinoline (1.38 g, 5.16 mmol) inCH₂Cl₂(50 mL) at −78° C. was added m-CPBA (77%) (1.25 g, 7.23 mmol) andthe mixture was allowed to slowly warm to RT (ca. 1 h). The mixture wasdiluted with CH₂Cl₂ and washed with saturated NaHCO₃. The organic layerwas dried over Na₂SO₄, filtered and concentrated under reduced pressure.The crude mixture was purified by silica gel chromatography usingCH₂Cl₂:MeOH 100:0 to 90:10 to afford7-methoxy-4-(phenylsulfinyl)quinoline as a off-white solid. MS found:M+H+=284.0.

EXAMPLE 61

Synthesis of (7-methoxyquinolin-4-yl)(4-nitrophenyl)methanol

To a solution of 7-methoxy-4-(phenylsulfinyl)quinoline (0.232 g, 0.819mmol) in THF (6 mL) at −78° C. was added phenylmagnesium chloride, 2.0 Min THF (0.819 ml, 1.64 mmol). After 5 min, the solution was warmed to RTfor 15 minutes. The solution was cooled to −78° C. and treated with4-nitrobenzaldehyde (0.371 g, 2.46 mmol). After 5 min, the solution waswarmed to RT. After 1 hr, the reaction was quenched with saturatedNH₄Cl. The mixture was diluted with CH₂Cl₂ and washed with water andbrine. The organic fraction was dried with Na₂SO₄ and concentrated invacuo. The yellow residue was purified by silica gel chromatographyusing 20-100% Hexanes:EtOAc to afford(7-methoxyquinolin-4-yl)(4-nitrophenyl)methanol as a white solid. MSfound M+H+=311.2.

EXAMPLE 62

Synthesis of 4-((7-methoxyquinolin-4-yl)methyl)benzenamine

A mixture of (7-methoxyquinolin-4-yl)(4-nitrophenyl)methanol (0.187 g,0.603 mmol) and tin(II) chloride dihydrate (0.823 g, 3.62 mmol) in MeOH(10 mL) was heated to 60° C. After 1 hr an additional 5 eq of tin(II)chloride dihydrate was added. After 3 hrs, the mixture was concentratedin vacuo and diluted with EtOAc and water. Saturated NaHCO₃ was addeduntil the aqueous layer was basic. The resulting suspension was filteredand the solids washed with EtOAc. The organic fraction was washed withwater, brine, and dried with Na₂SO₄. After concentrating in vacuo, thecrude, yellow solid, 4-((7-methoxyquinolin-4-yl)methyl)benzenamine wasadvanced without further purification. MS found: M+H+=265.1.

EXAMPLE 63

Synthesis of 7-chlorothieno[3,2-b]pyridine-2-carbonitrile

4-Chloro-7-methoxyquinoline-6-carboxamide was prepared in accordance toa procedure described in WO 01/94353.

EXAMPLE 64

Synthesis of2,2-dimethyl-5-((pyridin-4-ylamino)methylene)-1,3-dioxane-4,6-dione

In a dried 2-necked RBF equipped with reflux condenser and inertatmosphere, 2,2-dimethyl-1,3-dioxane-4,6-dione (2.33 g, 16 mmol) wasdissolved in triethyl orthoformate (16 ml, 97 mmol) and the mixture wasstirred at 100° C. under nitrogen for 1.5 h. On complete consumption ofstarting material (tic), pyridin-4-amine (1.5 g, 16 mmol) was added andheating continued for 4.5 h. The reaction mixture was cooled down to RTand poured into hexane (50 mL). The solid was filtered off and washedwith hexane to afford2,2-dimethyl-5-((pyridin-4-ylamino)methylene)-1,3-dioxane-4,6-dione asan orange solid.

EXAMPLE 65

Synthesis of 1,6-naphthyridin-4-ol

A solution of2,2-dimethyl-5-((pyridin-4-ylamino)methylene)-1,3-dioxane-4,6-dione(1.149 g, 4.63 mmol) in diphenyl ether was heated at 200° C. for 20 min,then cooled to RT. Hexane was added and the mixture was stirred at RTfor 30 mins. The solid was filtered off and washed with hexane tofurnish 1,6-naphthyridin-4-ol as an off-brown solid.

EXAMPLE 66

Synthesis of 4-chloro-1,6-naphthyridine

1,6-naphthyridin-4-ol (0.530 g, 3.63 mmol) was dissolved in phosphorusoxychloride (4.06 ml, 43.5 mmol) and heated at reflux for 14 h. ExcessPOCl₃ was removed under reduced pressure and the mixture was azeotropedwith toluene. The resultant gum was treated with sat. NaHCO₃ until nogas was generated. The mixture was extracted with EtOAc, the combinedextracts were washed with sodium bicarbonate and the solvent was removedunder reduced pressure. The crude product was purified via columnchromatography on silica gel (RediSep 40 g column, gradient elution with0-90% EtOAc/DCM) to afford 4-chloro-1,6-naphthyridine as a white solid.

EXAMPLE 67

Synthesis of 4(thieno[3,2-b]pyridin-7-ylthio)aniline

4-(Thieno[3,2-b]pyridin-7-ylthio)aniline was prepared using theprocedure described in Example 17. MS m/z=259 [M+H]⁺. Calc'd forC₁₃H₁₀N₂S₂: 258.36.

EXAMPLE 68

Synthesis of 7-(4-aminophenylthio)thieno[3,2-b]pyridine-2-carbonitrile

7-(4-Aminophenylthio)thieno[3,2-b]pyridine-2-was prepared using theprocedure described in Example 17. MS m/z=284 [M+H]⁺. Calc'd forC₁₄H₉N₃S₂: 283.37.

EXAMPLE 69

Synthesis of 4-chloro-5,7-dimethoxyquinoline Step 1:5-((3,5-Dimethoxyphenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

In a dried 2-necked round bottom flask equipped with reflux condenserand inert atmosphere, 2,2-dimethyl-1,3-dioxane-4,6-dione (5.3 g, 37mmol) was dissolved in triethyl orthoformate (37 ml, 221 mmol) and themixture was stirred at 100° C. under nitrogen for 1.5 h.3,5-Dimethoxybenzenamine (5.6 g, 37 mmol) was added and heatingcontinued for 4.5 h. The reaction mixture was cooled down to RT andpoured into hexane (50 mL). The solid was filtered off and washed withhexane to afford5-((3,5-dimethoxyphenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dioneas a light yellow solid. MS Found m/z=[M+H]⁺. 308.1 Calc'd forC₁₅H₁₇NO₆: 307.3.

Step 2: 5,7-Dimethoxyquinolin-4-ol

A solution of5-((3,5-dimethoxyphenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione(9.23 g, 30.0 mmol) in diphenyl ether was heated at 200° C. for 20 min.,then cooled down to RT. Hexane was added and the mixture was stirred atRT for 30 mins. The solvent was removed to furnish5,7-dimethoxyquinolin-4-ol as a light brown solid, which was used fornext step without further purification. MS Found m/z=[M+H]⁺. 206.2Calc'd for C₁₁H₁₁NO₃: 205.2.

Step 3: 4-Chloro-5,7-dimethoxiyquinoline

To a mixture of crude 5,7-dimethoxyquinolin-4-ol (5.36 g, 26 mmol) andHunig'sBase (9.1 ml, 52 mmol) in toluene, was added POCl₃(29 ml, 313mmol). The mixture was refluxed for 5 h. Excess POCl₃ was removed underreduced pressure and azeotroped with toluene. The resultant gum wastreated with sat. NaHCO₃ until no gas generated. The mixture wasextracted with EtOAc, the organic extracts were combined and washed withsodium bicarbonate and solvent removed under reduced pressure. The crudeproduct was purified via column chromatography on silica gel (RediSep120 g column, gradient elution with 0-50% EtOAc/DCM) to afford4-chloro-5,7-dimethoxyquinoline as a yellow solid. MS Found m/z=[M+H]⁺.224.2 Calc'd for C₁₁H₁₀ClN: 223.7.

EXAMPLE 70

Synthisis of 7-chloro-2-(trimethylsilyl)furo[3,2-b]pyridine Step 1:2-(Trimethylsilyl)furo[3,2-b]pyridine

A sealed pressure flask was charged with 2-bromopyridin-3-ol (10.0 g,57.5 mmol), ethynyltrimethylsilane (15.9 ml, 115 mmol), copper (I)iodide (1.09 g, 5.75 mmol), bis(triphenylphosphine)palladium(II)chloride (2.02 g, 2.87 mmol) and 7.5 mL of dioxane.Ethynyltrimethylsilane (15.9 ml, 115 mmol) and TEA (40.0 ml, 287 mmol)were added, the vial was flushed with nitrogen, and the reaction wasstirred at 50° C. for 18 h. The reaction was concentrated and purifiedvia column chromatography (gradient elution 0-40% EtOAc:Hex) to afford2-(trimethylsilyl)furo[3,2-b]pyridine as a brown oil. MS FoundM+H+=192.3

Step 2: 2-(Trimethylsilyl)furo[3,2-b]pyridine N-oxide

2-(Trimethylsilyl)furo[3,2-b]pyridine (14.68 g, 76.7 mmol) was dissolvedin 80 mL DCM and cooled to 0° C. m-CPBA (33.1 g, 192 mmol) was dissolvedin 160 mL DCM and slowly added to the reaction vessel. Upon completeaddition, the reaction was warmed to RT and stirred for three hours.Reaction was diluted with DCM and washed twice with saturated sodiumbicarbonate solution. 30 g of carbonate scavenger beads (—30 mmol) wereadded to the organic layer and the solution was stirred for 30 minutes.The reaction was filtered, washed with brine, dried with sodium sulfate,filtered, and concentrated. The material was purified via columnchromatography (gradient elution 0-10% MeOH:DCM) to afford2-(trimethylsilyl)furo[3,2-b]pyridine N-oxide as a light brown oil thatsolidified under high vacuum. MS: M+H+=208.2

Step 3: 7-Chloro-2-(trimethylsilyl)furo[3,2-b]pyridine

2-(Trimethylsilyl)furo[3,2-b]pyridine N-oxide (10.51 g, 50.7 mmol)dissolved in POCl₃ (47.3 ml, 507 mmol) in a sealed flask and heated at100° C. for one hour. The reaction was cooled to RT, poured into abeaker washing with minimal DCM, and cooled in a brine bath. Saturatedsodium bicarbonate solution was added very slowly and then solid sodiumbicarbonate was added portion wise until the solution was at about pH=8.The solution was extracted twice with DCM, and the combined organiclayers were dried with sodium sulfate, filtered, and concentrated. Thematerial was purified via column chromatography (gradient elution 5-40%EtOAc:Hex) to afford 7-chloro-2-(trimethylsilyl)furo[3,2-b]pyridine as apale yellow oil. MS: M+H+=226.2

EXAMPLE 71

Synthesis of 7-chloro-2-cyclopropylfuro[3,2-b]pyridine Step 1:7-Chloro-2-iodofuro[3,2-b]pyridine

7-Chloro-2-(trimethylsilyl)furo[3,2-b]pyridine (0.250 g, 1.11 mmol) andNIS (2.49 g, 11.1 mmol) were dissolved in 3 mL of ACN and stirred for 5minutes. Potassium fluoride (0.0708 g, 1.22 mmol) was added and thereaction was stirred at 50° C. for one hour. The reaction wasconcentrated, redissolved in ethyl acetate, and washed with saturatedsodium thiosulfate, water and brine. The organic layer was dried withsodium sulfate, filtered, and concentrated. The crude material waspurified via column chromatography (gradient elution 0-100% EtOAc:Hex)to afford 7-chloro-2-iodofuro[3,2-b]pyridine as a white solid. MS:M+H+=280.2.

Step 2: 7-Chloro-2-cyclopropylfuro[3,2-b]pyridine

7-Chloro-2-iodofuro[3,2-b]pyridine (0.130 g, 0.47 mmol),cyclopropylboronic acid (0.080 g, 0.93 mmol), and tricyclohexylphosphine(0.026 g, 0.093 mmol) were dissolved in 3 mL toluene and 1 mL water.Potassium phosphate (0.30 g, 1.4 mmol) was added followed by PdOAc2(0.010 g, 0.047 mmol), the reaction was flushed with argon, and thereaction stirred at 100° C. for 48 h. The reaction was cooled to RT andpartitioned between DCM and water. The layers were separated and theaqueous layer was extracted with DCM. The combined organic layers weredried with sodium sulfate, filtered, and concentrated. The crudematerial was purified via column chromatography (gradient elution 0-50%EtOAc:Hex) to afford 7-chloro-2-cyclopropylfuro[3,2-b]pyridine as anorange oil. MS: M+H+=194.4.

EXAMPLE 72

Synthesis of 7-chlorofuro[3,2-b]pyridine-2-carbonitrile

In a sealed tube 7-chloro-2-iodofuro[3,2-b]pyridine (0.200 g, 0.72mmol), KCN (0.093 g, 1.4 mmol), and copper (I) iodide (0.014 g, 0.072mmol) were dissolved in 2 mL DMF. Pd(Ph3P)₄(0.041 g, 0.036 mmol) wasadded, the tube was flushed with nitrogen, and the reaction in the tubewas stirred overnight at 100° C. The reaction was cooled to RT, dilutedwith DCM, and washed with water. The aqueous layer was extracted withDCM, and the combined organic layers were washed with brine, dried withsodium sulfate, filtered, and concentrated. The material was purifiedvia column chromatography (gradient elution 0-50% EtOAc:Hex) to afford7-chlorofuro[3,2-b]pyridine-2-carbonitrile as a white solid. MS:M+H+=179.4.

EXAMPLE 73

Synthesis of 7-chloro-2-methylfuro[3,2-b]pyridine

In an oven-dried round bottom flask, 7-chloro-2-iodofuro[3,2-b]pyridine(0.200 g, 0.72 mmol) was dissolved in 3 mL THF and cooled to −78° C.nBuLi (0.43 ml, 1.1 mmol) was slowly added and the reaction was stirredfor one hour. Meanwhile, a vial was filled with MeI and warmed to RT.Magnesium sulfate was added and the mixture was stirred for 5 minutesand filtered into another vial. Immediately from this vial, MeI (0.11ml, 1.8 mmol) was added to the reaction which was stirred at −78° C. for3 hours. The reaction was quenched with saturated ammonium chloridesolution and warmed to RT. DCM was added, the layers were separated, andthe aqueous layer was extracted twice with DCM. The combined organiclayers were dried with sodium sulfate, filtered, and concentrated. Thematerial was purified via column chromatography (gradient elution 0-50%EtOAc:Hex) to afford 7-chloro-2-methylfuro[3,2-b]pyridine as a lightbrown oil. MS: M+H+=168.3.

The Examples disclosed in Table I below are additional representativeexamples, of the present invention. These Examples were made by themethods indicated in Table I, which generally correlate to Methods A1-3,B1-5, C1-5 and D1a, D1b, D2 and D3 of Examples 29-45 herein. The MS datais the M+H⁺ ion value found for the example. Biological data is providedfor a majority of those compounds exemplified in Table I. It should beunderstood and appreciated by those of ordinary skill in the art thatthe data for compound examples 39, 174, 230, 248, 282, 311, 318, 323,333, 340-341, 347, 360 and 369 may not be completely accurate, aspresented herein, likely due to poor sample solubility, or otherpossible solution related issues, causing a decreased calculatedactivity. It is believed that these examples should be more active thanrecorded herein.

TABLE 1 24h_4NPloidy AurA_IC50_IP AurB_IC50_IP EC50_IP Ex. MS (uM (uM(uM No. Name Data Method Avg) Avg) Avg) 74 N-(4-((6,7-bis(methyloxy)-4-529 B3 0.014 0.032 0.018 quinolinyl)oxy)phenyl)-4-(3,4-dimethylphenyl)-1- phthalazinamine 75 N-(4-((6,7-bis(methyloxy)-4- 508B3 0.023 0.042 0.025 quinolinyl)oxy)phenyl)-4-(1-piperidinyl)-1-phthalazinamine 76 N-(4-((6,7-bis(methyloxy)-4- 525.1 B30.034 0.106 0.060 quinolinyl)oxy)-3- fluorophenyl)-4-(2-thienyl)-1-phthalazinamine 77 N-(4-((6,7-bis(methyloxy)-4- 537.1 B3 0.701 0.0793.087 quinolinyl)oxy)-3- fluorophenyl)-4-(3,5-dimethyl-1H-pyrazol-1-yl)-1- phthalazinamine 78 7-((2-fluoro-4-((4-phenyl-1- 508B3 0.022 0.004 0.031 phthalazinyl)amino)phenyl)oxy)thieno[3,2-b]pyridine-2- carboxamide 79 N-(4-((7-(methyloxy)-1,5- 472 B3 0.0280.008 0.041 naphthyridin-4-yl)oxy)phenyl)- 4-phenyl-1-phthalazinamine 40N-(7-(methyloxy)-1,5- 471 C4 0.044 0.007 0.070 naphthyridin-4-yl)-N′-(4-phenyl-1-phthalazinyl)-1,4- benzenediamine 80 4-(5-fluoro-2- 520 B30.414 0.041 0.487 (methyloxy)phenyl)-N-(4-((7-(methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)-1- phthalazinamine 81N-(4-((7-(methyloxy)-1,5- 486 B3 0.012 0.006 0.008naphthyridin-4-yl)oxy)phenyl)- 4-(4-methylphenyl)-1- phthalazinamine 82N-(4-((7-(methyloxy)-1,5- 493 B3 0.013 0.006 0.061naphthyridin-4-yl)oxy)phenyl)- 4-(4-methyl-1,3-thiazol-2-yl)-1-phthalazinamine 83 4-ethyl-N-(6-((7-(methyloxy)- 451 C2 0.080 0.0100.349 1,5-naphthyridin-4-yl)oxy)-3- pyridinyl)-6-phenyl-3-pyridazinamine 84 N-(5-((7-(methyloxy)-1,5- 474 unique 0.160 0.002 0.485naphthyridin-4-yl)oxy)-2- pyrimidinyl)-4-phenyl-1- phthalazinamine 467-((4-((4-phenyl-1- 490 unique 0.015 0.001 0.171phthalazinyl)amino)phenyl)oxy)thieno[3, 2-b]pyridine-2- carboxamide 85N-(4-((7-(methyloxy)-1,5- 494 B1 0.066 0.004 0.085naphthyridin-4-yl)oxy)phenyl)- 4-(4-methyl-1-piperazinyl)-1-phthalazinamine 86 4-((4-((4-(4-methyl-1,3- 487 B3 0.031 0.014 0.097thiazol-2-yl)-1- phthalazinyl)amino)phenyl)oxy)- 7-quinolinecarbonitrile87 4-((4-((4-(5-fluoro-2- 514 B3 0.142 0.013 (methyloxy)phenyl)-1-phthalazinyl)amino)phenyl)oxy)- 7-quinolinecarbonitrile 884-((4-((4-(4-methylphenyl)-1- 480 B3 0.006 0.003 0.006phthalazinyl)amino)phenyl)oxy)- 7-quinolinecarbonitrile 89N-(3-fluoro-4-((7-(methyloxy)- 490.1 B3 0.012 0.007 0.0521,5-naphthyridin-4- yl)oxy)phenyl)-4-phenyl-1- phthalazinamine 90N-(4-((6,7-bis(methyloxy)-4- 501 B3 0.019 0.025 0.013quinolinyl)oxy)phenyl)-4- phenyl-1-phthalazinamine 36N~5~-(7-(methyloxy)-1,5- 473 B5 0.038 0.004 0.326naphthyridin-4-yl)-N~2~-(4- phenyl-1-phthalazinyl)-2,5-pyrimidinediamine 91 N-(4-((7-(methyloxy)-4- 471 B3 0.054 0.012 0.030quinolinyl)oxy)phenyl)-4- phenyl-1-phthalazinamine 924-(hexahydropyrrolo[1,2- 520 B1 0.007 0.003 0.054a]pyrazin-2(1H)-yl)-N-(4-((7- (methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1- phthalazinamine 93 4-((4-((4-(3-hydroxyphenyl)-1-482 B3 0.008 0.001 0.025 phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile 94 4-((4-((4-(4-methyl-1- 488 B1 0.027 0.0010.090 piperazinyl)-1- phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile 95 4-((4-((4-(4-methyl-1,3- 505 Example 0.0270.002 0.167 thiazol-2-yl)-1- 47 phthalazinyl)amino)phenyl)oxy)-7-quinolinecarboxamide 47 4-((4-((4-(5-fluoro-2- 532 unique 5.000 0.1381.200 (methyloxy)phenyl)-1- phthalazinyl)amino)phenyl)oxy)-7-quinolinecarboxamide 96 N-(4-((7-(methyloxy)-1,6- 472.1 C1 0.026 0.0050.063 naphthyridin-4-yl)oxy)phenyl)- 4-phenyl-1-phthalazinamine 974-((8aS)- 520 B1 0.010 0.002 0.026 hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(4-((7- (methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1- phthalazinamine 98 N-(4-((6,7-bis(methyloxy)-4-502.1 C1 0.016 0.007 0.019 quinazolinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine 99 N-(4-((7-(methyloxy)-1,5- 503 C2 0.010 0.0020.023 naphthyridin-4-yl)oxy)phenyl)- 4-(6-(methyloxy)-2-pyridinyl)-1-phthalazinamine 100 4-(6-(methyloxy)-2-pyridinyl)- 502 C2 0.038 0.0060.020 N-(4-((7-(methyloxy)-4- quinolinyl)oxy)phenyl)-1- phthalazinamine101 N-(4-((6,7-bis(methyloxy)-4- 532 B3 0.010 0.010 0.009quinolinyl)oxy)phenyl)-4-(6- (methyloxy)-2-pyridinyl)-1- phthalazinamine102 4-((4-((4-(6-(methyloxy)-2- 497 B3 0.028 0.003 0.028 pyridinyl)-1-phthalazinyl)amino)phenyl)oxy)- 7-quinolinecarbonitrile 103N-(4-((7-(methyloxy)-1,6- 487 C2 0.035 0.004 0.030naphthyridin-4-yl)oxy)phenyl)- 4-(5-methyl-2-pyridinyl)-1-phthalazinamine 104 N-(4-((6,7-bis(methyloxy)-4- 517 B3 0.036 0.0420.020 quinolinyl)thio)phenyl)-4- phenyl-1-phthalazinamine 1054-((4-((4-phenyl-1- 466 C1 0.039 0.003 0.036phthalazinyl)amino)phenyl)oxy)- 7-quinolinecarbonitrile 106N-(4-((6,7-bis(methyloxy)-4- 557 B3 0.010 0.038 0.033quinolinyl)oxy)phenyl)-4-(4- (1,1-dimethylethyl)phenyl)-1-phthalazinamine 38 4-(4-(1,1- 528 C2 0.023 0.017 0.080dimethylethyl)phenyl)-N-(4- ((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)- 1-phthalazinamine 107 4-methyl-N-(4-((7-436 C2 0.018 0.005 0.390 (methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-6-phenyl-3- pyridazinamine 1084-ethyl-N-(4-((7-(methyloxy)- 450 C2 0.016 0.004 0.0831,5-naphthyridin-4- yl)oxy)phenyl)-6-phenyl-3- pyridazinamine 109N-(4-((7-(methyloxy)-1,6- 494 C2 0.060 0.001 0.297naphthyridin-4-yl)oxy)phenyl)- 4-(4-methyl-1-piperazinyl)-1-phthalazinamine 110 N-(4-((7-(methyloxy)-1,6- 487.1 C2 0.043 0.002 0.124naphthyridin-4-yl)oxy)phenyl)- 4-(6-methyl-2-pyridinyl)-1-phthalazinamine 111 N-(4-((7-(methyloxy)-1,5- 487.1 C2 0.040 0.005 0.109naphthyridin-4-yl)oxy)phenyl)- 4-(6-methyl-2-pyridinyl)-1-phthalazinamine 112 (6-(4-((4-((6,7-bis(methyloxy)- 532 B3 0.015 0.0030.020 4- followed quinolinyl)oxy)phenyl)amino)- by 1-phthalazinyl)-2-hydrolysis pyridinyl)methanol 113 (6-(4-((4-((6,7-bis(methyloxy)- 573 B30.014 0.011 0.048 4- quinolinyl)oxy)phenyl)amino)- 1-phthalazinyl)-2-pyridinyl)methyl acetate 114 (6-(4-((4-((7-(methyloxy)-1,5- 503 B3 0.0360.005 0.390 naphthyridin-4- followed yl)oxy)phenyl)amino)-1- byphthalazinyl)-2- hydrolysis pyridinyl)methanol 115 N-(3-fluoro-4-(4- 459B3 0.163 0.006 0.116 quinolinyloxy)phenyl)-4- phenyl-1-phthalazinamine116 N-(4-((7-(methyloxy)-1,5- 487 B3 0.062 0.011 0.179naphthyridin-4-yl)oxy)phenyl)- 4-(4-methyl-2-pyridinyl)-1-phthalazinamine 117 N-(4-((6,7-bis(methyloxy)-4- 516 B3 0.057 0.0430.066 quinolinyl)oxy)phenyl)-4-(4- methyl-2-pyridinyl)-1-phthalazinamine 118 N-(4-((7-(methyloxy)-4- 486 B3 0.136 0.009 0.110quinolinyl)oxy)phenyl)-4-(4- methyl-2-pyridinyl)-1- phthalazinamine 1194-((4-((4-(2- 496 B3 0.175 0.007 1.200 (methyloxy)phenyl)-1-phthalazinyl)amino)phenyl)oxy)- 7-quinolinecarbonitrile 1204-(6-((methyloxy)methyl)-2- 517 B3 0.019 0.003 0.305pyridinyl)-N-(4-((7- (methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)-1-phthalazinamine 121 N-(4-((7-(methyloxy)-1,6- 487 C2 0.041 0.007 0.132naphthyridin-4-yl)oxy)phenyl)- 4-(4-methyl-2-pyridinyl)-1-phthalazinamine 122 4-((4-((4-(5-methyl-2- 481 B3 0.022 0.003 0.053pyridinyl)-1- phthalazinyl)amino)phenyl)oxy)- 7-quinolinecarbonitrile123 N-(4-((6,7-bis(methyloxy)-4- 517 C2 0.132 0.015 0.077quinazolinyl)oxy)phenyl)-4-(4- methyl-2-pyridinyl)-1- phthalazinamine124 N-(7-(methyloxy)-1,6- 471 0.042 0.002 0.025naphthyridin-4-yl)-N′-(4- phenyl-1-phthalazinyl)-1,4- benzenediamine 125N-(4-((7-(methyloxy)-1,5- 487 B3 0.018 0.003 0.059naphthyridin-4-yl)oxy)phenyl)- 4-(5-methyl-2-pyridinyl)-1-phthalazinamine 126 3-(methyloxy)-8-((4-((4-(4- 485 C2 0.388 0.017 1.200methylphenyl)-1- phthalazinyl)methyl)phenyl)oxy)- 1,5-naphthyridine 127N-(6-((7-(methyloxy)-1,6- 488.1 C2 0.241 0.009 1.200naphthyridin-4-yl)oxy)-3- pyridinyl)-4-(6-methyl-2-pyridinyl)-1-phthalazinamine 128 N-(6-((7-(methyloxy)-1,5- 488 C2 0.0990.018 1.200 naphthyridin-4-yl)oxy)-3- pyridinyl)-4-(6-methyl-2-pyridinyl)-1-phthalazinamine 129 N-(4-((7-(methyloxy)-1,5- 503 B3 0.1650.014 0.181 naphthyridin-4-yl)oxy)phenyl)-4-(5-(methyloxy)-3-pyridinyl)- 1-phthalazinamine 130N-(4-((7-(methyloxy)-1,5- 503 B3 0.654 0.100 1.200naphthyridin-4-yl)oxy)phenyl)- 4-(3-(methyloxy)-4-pyridinyl)-1-phthalazinamine 131 N-(4-((7-(methyloxy)-1,6- 503 C2 0.019 0.003naphthyridin-4-yl)oxy)phenyl)- 4-(6-(methyloxy)-2-pyridinyl)-1-phthalazinamine 132 (6-(4-((4-((7-(methyloxy)-1,5- 545 B3 0.022 0.0050.323 naphthyridin-4- yl)oxy)phenyl)amino)-1- phthalazinyl)-2-pyridinyl)methyl acetate 133 N-(4-((7-bromo-4- 519, 521 C2 0.494 0.0280.116 quinolinyl)oxy)phenyl)-4- phenyl-1-phthalazinamine 134N-(4-((6-bromo-4- 519, 521 C2 0.176 0.024 0.091quinolinyl)oxy)phenyl)-4- phenyl-1-phthalazinamine 135N-(5-((7-(methyloxy)-1,5- 473 0.063 0.012 0.449naphthyridin-4-yl)oxy)-2- pyridinyl)-4-phenyl-1- phthalazinamine 1364-(2,2-dimethyl-2,3-dihydro-1- 542 A1 0.037 0.016 0.099benzofuran-5-yl)-N-(4-((7- (methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1- phthalazinamine 137 4-(4-((1- 530 A1 0.091 0.0180.850 methylethyl)oxy)phenyl)-N-(4- ((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)- 1-phthalazinamine 138N-(4-((7-(methyloxy)-1,5- 492 B3 0.018 0.013 0.030naphthyridin-4-yl)oxy)phenyl)- 4-(5-methyl-2-thienyl)-1- phthalazinamine139 N-(4-((7-(methyloxy)-1,5- 502 A1 0.018 0.006 0.057naphthyridin-4-yl)oxy)phenyl)- 4-(3-(methyloxy)phenyl)-1-phthalazinamine 140 4-(5-chloro-2-thienyl)-N-(4- 512 A1 0.022 0.0080.022 ((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 141 4-((4-((4-(4- 496 C1 0.019 0.004 0.025(methyloxy)phenyl)-1- phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile 142 4-(1-benzothien-5-yl)-N-(4- 528 A1 0.0080.007 0.007 ((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 143 4-(1-methyl-1H-indol-2-yl)-N- 525 A1 0.012 0.0090.094 (4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 144 N-(4-((7-(methyloxy)-1,5- 471.1 C1 0.061 0.0200.155 naphthyridin-4-yl)oxy)phenyl)- 4-phenyl-1-isoquinolinamine 145N-(4-((7-(methyloxy)-1,6- 471.1 C1 0.326 0.096 1.200naphthyridin-4-yl)oxy)phenyl)- 4-phenyl-1-isoquinolinamine 146N-(4-((7-(methyloxy)-1,5- 540.1 C1 0.026 0.008 0.057naphthyridin-4-yl)oxy)phenyl)- 4-(4-(trifluoromethyl)phenyl)-1-phthalazinamine 147 4-((4-((4-(4- 534.2 C1 0.025 0.011 0.020(trifluoromethyl)phenyl)-1- phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile 148 N-(4-((6,7-bis(methyloxy)-4- 480 C1 0.0620.016 0.039 quinazolinyl)oxy)phenyl)-4- ethyl-6-phenyl-3- pyridazinamine29 3-(4-((4-((7-(methyloxy)-1,5- 497 A1 0.139 0.018 0.442naphthyridin-4- yl)oxy)phenyl)amino)-1- phthalazinyl)benzonitrile 1494-((4-((4-ethyl-6-phenyl-3- 444 C1 0.146 0.014 0.420pyridazinyl)amino)phenyl)oxy)- 7-quinolinecarbonitrile 150N-(4-((6,7-bis(methyloxy)-4- 516.2 B3 0.014 0.007 0.017quinolinyl)oxy)phenyl)-4-(6- methyl-2-pyridinyl)-1- phthalazinamine 37N-(4-((7-(methyloxy)-1,5- 502 C1 0.020 0.004 0.052naphthyridin-4-yl)oxy)phenyl)- 4-(4-(methyloxy)phenyl)-1-phthalazinamine 151 N-(4-((7-(methyloxy)-1,5- 479 B1 0.022 0.005 0.128naphthyridin-4-yl)oxy)phenyl)- 4-(1-piperidinyl)-1- phthalazinamine 152N-(4-((7-(methyloxy)-1,5- 492 C2 0.006 0.006 0.009naphthyridin-4-yl)oxy)phenyl)- 4-(4-methyl-2-thienyl)-1- phthalazinamine153 N-(4-((6,7-bis(methyloxy)-4- 522 C2 0.009 0.012 0.001quinazolinyl)oxy)phenyl)-4-(4- methyl-2-thienyl)-1- phthalazinamine 1542-chloro-5-(4-((4-((7- 531 A1 0.018 0.004 0.061(methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)amino)-1-phthalazinyl)benzonitrile 155 4-(4-(1-methylethyl)phenyl)-N- 514 B10.029 0.011 0.068 (4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 49 4-((4-((4-ethyl-6-phenyl-3- 462 unique 0.021 0.0010.028 pyridazinyl)amino)phenyl)oxy)- 7-quinolinecarboxamide 156N-(4-((7-(methyloxy)-1,5- 464 C2 0.047 0.005 0.061naphthyridin-4-yl)oxy)phenyl)- 6-phenyl-4-propyl-3- pyridazinamine 324-(1-azepanyl)-N-(4-((7- 493 B1 0.016 0.009 0.036(methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)-1- phthalazinamine 1574-(4-methyl-3,4-dihydro-2H- 543.1 A1 0.012 0.005 0.0281,4-benzoxazin-7-yl)-N-(4-((7- (methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1- phthalazinamine 158 N-(4-((7-(methyloxy)-1,5- 503 A10.037 0.005 0.075 naphthyridin-4-yl)oxy)phenyl)-4-(6-(methyloxy)-3-pyridinyl)- 1-phthalazinamine 1594-(1-benzofuran-5-yl)-N-(4- 512 A1 0.010 0.007 0.007((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)- 1-phthalazinamine160 4-(4-chlorophenyl)-N-(4-((7- 506 A1 0.007 0.003 0.005(methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)-1- phthalazinamine 161N-(3-fluoro-4-(4- 473 B3 0.027 0.005 0.010 quinolinyloxy)phenyl)-4-(4-methylphenyl)-1- phthalazinamine 162 4-((4-((4-(5-methyl-2-thienyl)- 486B3 0.012 0.004 0.004 1- phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile 163 N-(4-((7-(methyloxy)-1,5- 556 A1 0.072 0.0091.200 naphthyridin-4-yl)oxy)phenyl)- 4-(4-((trifluoromethyl)oxy)phenyl)- 1-phthalazinamine 164N-(4-((3-fluoro-7-(methyloxy)- 489.1 C1 0.040 0.003 0.0764-quinolinyl)oxy)phenyl)-4- phenyl-1-phthalazinamine 1654-(1,3-benzodioxol-5-yl)-N-(4- 516.1 A1 0.009 0.007 0.006((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)- 1-phthalazinamine166 4-(2,3-dihydro-1,4- 530 A1 0.023 0.006 0.087benzodioxin-6-yl)-N-(4-((7- (methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1- phthalazinamine 167 4-(1H-indol-5-yl)-N-(4-((7- 511A1 0.013 0.004 0.027 (methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)-1-phthalazinamine 168 4-(2,3-dihydro-1-benzofuran- 514 A1 0.008 0.0050.007 5-yl)-N-(4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 169 4-(1-benzothien-3-yl)-N-(4- 528 A1 0.010 0.0090.027 ((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 170 4-((4-((4-(4-methyl-2-thienyl)- 486 B3 0.016 0.0090.007 1- phthalazinyl)amino)phenyl)oxy)- 7-quinolinecarbonitrile 1714-(1-benzothien-2-yl)-N-(4- 528 A1 0.013 0.015 0.004((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)- 1-phthalazinamine172 4-(3-chloro-4- 574 A1 0.039 0.017 0.034(trifluoromethyl)phenyl)-N-(4- ((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)- 1-phthalazinamine 41N-(6-((7-(methyloxy)-1,5- 473 C5 0.079 0.009 0.195naphthyridin-4-yl)oxy)-3- pyridinyl)-4-phenyl-1- phthalazinamine 173N-(4-((7-(methyloxy)-1,5- 533 C2 0.019 0.019 0.006naphthyridin-4-yl)oxy)phenyl)- 4-((4aR,8aR)-octahydro-2(1H)-isoquinolinyl)-1- phthalazinamine 174 4-(5-(4-phenylphthalazin-1-467 C5 25.000 5.000 1.200 ylamino)pyridin-2-yloxy)quinoline-7-carbonitrile 175 4-(2-(ethyloxy)-1,3-thiazol-4- 523 A20.013 0.003 0.059 yl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)- 1-phthalazinamine 1764-(1-benzofuran-2-yl)-N-(4- 512.2 A1 0.007 0.002 0.008((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)- 1-phthalazinamine177 4-(4-((4-((7-(methyloxy)-1,5- 515.2 A1 0.206 0.004 1.200naphthyridin-4- yl)oxy)phenyl)amino)-1- phthalazinyl)benzamide 1784-(2-fluoro-6-methyl-3- 505.1 A1 0.035 0.002 0.027 pyridinyl)-N-(4-((7-(methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)-1- phthalazinamine 179N-(4-((2-fluoro-4-((4-phenyl-1- 537 unique 0.180 0.043 0.226phthalazinyl)amino)phenyl)oxy)- 2-pyridinyl)-4- morpholinecarboxamide180 4-(4-fluoro-3- 520 A1 0.027 0.004 0.025 (methyloxy)phenyl)-N-(4-((7-(methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)-1- phthalazinamine 1814-(4-((4-((7-(methyloxy)-1,5- 497 A1 0.171 0.007 0.104 naphthyridin-4-yl)oxy)phenyl)amino)-1- phthalazinyl)benzonitrile 182N-(4-((7-(methyloxy)-1,5- 523 A1 0.023 0.002 0.032naphthyridin-4-yl)oxy)phenyl)- 4-(3-quinolinyl)-1- phthalazinamine 1834-(1H-indol-4-yl)-N-(4-((7- 511 A1 0.033 0.003 0.052(methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)-1- phthalazinamine 1844-((4-((4-(3-methyl-2-thienyl)- 486 B3 0.201 0.003 0.130 1-phthalazinyl)amino)phenyl)oxy)- 7-quinolinecarbonitrile 185N-(4-((7-(methyloxy)-1,5- 492 C2 0.231 0.006 0.241naphthyridin-4-yl)oxy)phenyl)- 4-(3-methyl-2-thienyl)-1- phthalazinamine186 N-(3-fluoro-4-(4- 490 B3 0.059 0.002 0.031quinolinyloxy)phenyl)-4-(6- (methyloxy)-2-pyridinyl)-1- phthalazinamine187 N-(3-fluoro-4-((7-(methyloxy)- 504 B3 0.006 0.004 0.0061,5-naphthyridin-4- yl)oxy)phenyl)-4-(4- methylphenyl)-1-phthalazinamine 39 N-(4-((3-fluoro-7-(methyloxy)- 557 C3 25.000 1.0001.200 4-quinolinyl)oxy)phenyl)-4-(4- (trifluoromethyl)phenyl)-1-phthalazinamine 42 N-(4-((7-(4-morpholinyl)-4- 526 D1 0.011 0.002 0.007quinolinyl)oxy)phenyl)-4- phenyl-1-phthalazinamine 1884-(3,5-dimethylphenyl)-N-(4- 500 A1 0.017 0.006 0.051((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)- 1-phthalazinamine189 N-(4-((7-(methyloxy)-1,5- 493 A2 0.022 0.009 0.191naphthyridin-4-yl)oxy)phenyl)- 4-(5-methyl-1,3-thiazol-2-yl)-1-phthalazinamine 190 4-(6-fluoro-3-pyridinyl)-N-(4- 491.1 A1 0.0520.005 0.129 ((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 191 4-(2-fluoro-3-pyridinyl)-N-(4- 491.1 A1 0.1040.009 1.200 ((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 192 4-(3,4-dimethylphenyl)-N-(4- 500.1 A1 0.005 0.0050.005 ((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 193 4-(3-chloro-4-fluorophenyl)-N- 524.1 A1 0.0230.005 0.027 (4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 194 4-(4-(dimethylamino)phenyl)- 515 A1 0.023 0.0100.033 N-(4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 195 4-(2-methyl-1,3-benzothiazol- 543 A1 0.088 0.0050.197 5-yl)-N-(4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 196 4-((4-((6-phenyl-4-propyl-3- 458 C1 0.672 0.0060.342 pyridazinyl)amino)phenyl)oxy)- 7-quinolinecarbonitrile 197N-(4-((7-(methyloxy)-1,5- 555 A1 0.034 0.021naphthyridin-4-yl)oxy)phenyl)- 4-(3-(1-piperidinyl)phenyl)-1-phthalazinamine 198 N-(4-((7-(methyloxy)-1,5- 555 A1 0.128 0.004 0.399naphthyridin-4-yl)oxy)phenyl)- 4-(4-(1-piperidinyl)phenyl)-1-phthalazinamine 199 4-ethyl-N-(4-((7-(methyloxy)- 464 B4 0.027 0.0020.018 1,5-naphthyridin-4- yl)oxy)phenyl)-6-(4- methylphenyl)-3-pyridazinamine 200 N-(4-((7-(methyloxy)-1,5- 463 A2 0.087 0.003 0.314naphthyridin-4-yl)oxy)phenyl)- 4-(1,3-oxazol-2-yl)-1- phthalazinamine201 4-(3,4-dichlorophenyl)-N-(4- 540 A1 0.035 0.006 0.022((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)- 1-phthalazinamine202 N-(4-((2-(1-methyl-1H- 527 B3 0.020 0.002 0.011imidazol-5-yl)thieno[3,2- b]pyridin-7-yl)oxy)phenyl)-4-phenyl-1-phthalazinamine 203 N-(4-((2-(1-methyl-1H- 541.2 B3 0.008 0.0020.002 imidazol-5-yl)thieno[3,2- b]pyridin-7-yl)oxy)phenyl)-4-(4-methylphenyl)-1- phthalazinamine 204 4-(1-methyl-1H-indol-5-yl)-N-525 A1 0.026 0.003 0.021 (4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)- 1-phthalazinamine 2054-ethyl-N-(4-((7-(methyloxy)- 470 B4 0.060 0.004 0.0741,5-naphthyridin-4- yl)oxy)phenyl)-6-(5-methyl-2-thienyl)-3-pyridazinamine 30 4-(1-methyl-1H-imidazol-2-yl)- 476 A2 1.3871.200 N-(4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 206 4-(1H-indol-6-yl)-N-(4-(7- 511 A1 0.017 0.0030.002 methoxy-1,5-naphthyridin-4- yloxy)phenyl)phthalazin-1- amine 207N-(4-((7-(methyloxy)-1,5- 488 B3 0.060 0.009 0.005naphthyridin-4-yl)thio)phenyl)- 4-phenyl-1-phthalazinamine 2084-((4-((4-phenyl-1- 482 B3 0.180 0.007 0.023phthalazinyl)amino)phenyl)thio)- 7-quinolinecarbonitrile 2094-(3-amino-4-methylphenyl)- 500 A1 0.012 0.001 0.004N-(4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 210 4-ethyl-N-(4-((7-(methyloxy)- 470 B4 0.031 0.0020.056 1,5-naphthyridin-4- yl)oxy)phenyl)-6-(4-methyl-2-thienyl)-3-pyridazinamine 211 7-(methyloxy)-4-((4-((4-(4- 528.1 B3 0.0060.001 0.002 methylphenyl)-1- phthalazinyl)amino)phenyl)oxy)-6-quinolinecarboxamide 212 N-(4-((7-(methyloxy)-1,5- 462 A1 0.478 0.0180.501 naphthyridin-4-yl)oxy)phenyl)- 4-(1H-pyrazol-4-yl)-1-phthalazinamine 213 4-(3-methyl-4- 516 A1 0.079 0.011 0.044(methyloxy)phenyl)-N-(4-((7- (methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1- phthalazinamine 214 4-(3,4-difluorophenyl)-N-(4- 508A1 0.085 0.007 0.033 ((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 215 N-(4-((7-(methyloxy)-1,5- 474 A1 0.743 0.024 1.200naphthyridin-4-yl)oxy)phenyl)- 4-(5-pyrimidinyl)-1- phthalazinamine 216N-(4-((7-(methyloxy)-1,5- 476 A1 0.160 0.006 0.074naphthyridin-4-yl)oxy)phenyl)- 4-(1-methyl-1H-pyrazol-4-yl)-1-phthalazinamine 217 4-((4-((4-(4-cyanophenyl)-1- 491 A1 0.454 0.0160.369 phthalazinyl)amino)phenyl)oxy)- 7-quinolinecarbonitrile 218N-(4-((7-(methyloxy)-1,5- 478 B4 0.027 0.003 0.061naphthyridin-4-yl)oxy)phenyl)- 4-phenylthieno[2,3- d]pyridazin-7-amine219 4-(3-chlorophenyl)-N-(4-((7- 506.1 A1 0.051 0.010 0.031(methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)-1- phthalazinamine 2204-(4-fluorophenyl)-N-(4-((7- 490.1 A1 0.047 0.004 0.036(methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)-1- phthalazinamine 2214-(4-ethylphenyl)-N-(4-((7- 500.1 A1 0.026 0.007 0.015(methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)-1- phthalazinamine 2224-(4-chlorophenyl)-N-(6-((7- 507 C5 0.047 0.006 0.026(methyloxy)-1,5-naphthyridin- 4-yl)oxy)-3-pyridinyl)-1- phthalazinamine223 N-(4-((7-(methyloxy)-1,5- 476 A1 1.327 0.039 1.200naphthyridin-4-yl)oxy)phenyl)- 4-(1-methyl-1H-pyrazol-5-yl)-1-phthalazinamine 224 4-(3-chloro-4-methylphenyl)- 520 A1 0.034 0.0110.007 N-(4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 225 7-(methyloxy)-4-((4-((4- 513.5 B3 0.023 0.0040.004 phenyl-1- phthalazinyl)amino)phenyl)oxy)- 6-quinolinecarboxamide226 N,N-dimethyl-3-(4-((4-((7- 543 A1 0.187 0.014 1.200(methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)amino)-1-phthalazinyl)benzamide 227 4-(3-fluoro-4- 520 A1 0.051 0.003 0.061(methyloxy)phenyl)-N-(4-((7- (methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1- phthalazinamine 228 4-(5-chloro-2-pyridinyl)-N-(4-507 B3 0.034 0.004 0.035 ((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)- 1-phthalazinamine 2294-(5-ethyl-2-thienyl)-N-(4-((7- 506 B3 0.024 0.007 0.026(methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)-1- phthalazinamine 2304-phenyl-N-(4-(5,6,7,8- 446.2 B3 5.000 0.031tetrahydro-1,5-naphthyridin-4- yloxy)phenyl)-1- phthalazinamine 2314-((4-((4-(4-chloro-3- 525 A1 0.379 0.032 0.067 cyanophenyl)-1-phthalazinyl)amino)phenyl)oxy)- 7-quinolinecarbonitrile 2324-(4-chlorophenyl)-N-(4-((7- 522 B3 0.036 0.015 0.004(methyloxy)-1,5-naphthyridin- 4-yl)thio)phenyl)-1- phthalazinamine 2334-(4-chloro-2-methylphenyl)- 520 A1 0.845 0.021 0.600N-(4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 234 4-(1-methylethyl)-N-(4-((7- 464 B4 0.173 0.0060.196 (methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)-6-phenyl-3-pyridazinamine 235 4-(6-chloro-3-pyridinyl)-N-(4- 507.2 A1 0.123 0.0030.058 ((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 236 4-(4-chloro-3-methylphenyl)- 520.1 A1 0.027 0.0080.011 N-(4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 237 N-(4-((7-(methyloxy)-1,5- 518 A1 0.038 0.005 0.030naphthyridin-4-yl)oxy)phenyl)- 4-(4-(methylthio)phenyl)-1-phthalazinamine 238 N-(4-((6-(methyloxy)-4- 471 B3 0.265 0.005 0.053quinolinyl)oxy)phenyl)-4- phenyl-1-phthalazinamine 2394-(4-chlorophenyl)-N-(4-((6- 505 B3 0.120 0.008 0.001 (methyloxy)-4-quinolinyl)oxy)phenyl)-1- phthalazinamine 314-(3,3-dimethyl-1-butyn-1-yl)- 476 A3 0.033 0.008 0.045N-(4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 240 N-(4-((2-(1-methyl-1H- 558 B3 0.006 0.001 0.010imidazol-5-yl)thieno[3,2- b]pyridin-7-yl)oxy)phenyl)-4-(6-(methyloxy)-2-pyridinyl)-1- phthalazinamine 2414-(4-chlorophenyl)-N-(4-(1H- 464 B3 0.089 0.001 0.101pyrrolo[2,3-b]pyridin-4- yloxy)phenyl)-1- phthalazinamine 2424-((4-((4-(4-chlorophenyl)-1- 500 A1 0.173 0.022 0.019phthalazinyl)amino)phenyl)oxy)- 7-quinolinecarbonitrile 2434-(3-fluoro-4-methylphenyl)- 504 A1 0.014 0.005 0.006N-(4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 244 4-(4-chlorophenyl)-N-(3- 492 B3 0.048 0.003 0.040fluoro-4-(4- quinolinyloxy)phenyl)-1- phthalazinamine 245N-(4-((7-bromo-1,5- 522.1 B3 0.153 0.006 0.381naphthyridin-4-yl)oxy)phenyl)- 4-phenyl-1-phthalazinamine 51N-methyl-N-(7-(methyloxy)- 485.2 unique 0.860 0.023 0.3721,5-naphthyridin-4-yl)-N′-(4- phenyl-1-phthalazinyl)-1,4- benzenediamine246 4-(4-fluoro-3-methylphenyl)- 504 A1 0.032 0.008 0.030N-(4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 247 N-methyl-N-(7-(methyloxy)- 505.1 Example 0.2190.032 0.112 1,5-naphthyridin-4-yl)-N′-(4- 51 (4-methyl-2-thienyl)-1-phthalazinyl)-1,4- benzenediamine 53 N-(4-(1,5-naphthyridin-4- 442.1unique 0.153 0.003 0.105 yloxy)phenyl)-4-phenyl-1- phthalazinamine 2484-((4-((4-(4-chlorophenyl)-1- 517 B3 25.000 25.000 0.022phthalazinyl)amino)phenyl)thio)- 7-quinolinecarbonitrile 2494-(4-chlorophenyl)-N-(4-((2- 561 B3 0.004 0.001 0.008(1-methyl-1H-imidazol-5- yl)thieno[3,2-b]pyridin-7- yl)oxy)phenyl)-1-phthalazinamine 250 4-(4-chlorophenyl)-N-(4- 481 B3 0.094 0.003 0.031(thieno[3,2-b]pyridin-7- yloxy)phenyl)-1- phthalazinamine 2514-phenyl-N-(4-(thieno[3,2- 447.1 B3 0.376 0.004 0.227b]pyridin-7-yloxy)phenyl)-1- phthalazinamine 2524-(4-methylphenyl)-N-(4- 461 B3 0.077 0.005 0.027(thieno[3,2-b]pyridin-7- yloxy)phenyl)-1- phthalazinamine 2534-(4-chloro-2- 536 A1 0.173 0.009 0.835 (methyloxy)phenyl)-N-(4-((7-(methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)-1- phthalazinamine 448-((4-((4-phenyl-1- 467 D2 0.332 0.015 1.200phthalazinyl)amino)phenyl)oxy)- 1,5-naphthyridine-3- carbonitrile 254N-(4-((6,7-bis(methyloxy)-4- 502.1 C1 1.641 0.253 1.200cinnolinyl)oxy)phenyl)-4- phenyl-1-phthalazinamine 255N-(4-((2-(1-methyl-1H- 542 B3 0.005 0.000 0.014imidazol-5-yl)thieno[3,2- b]pyridin-7-yl)oxy)phenyl)-4-(5-methyl-2-pyridinyl)-1- phthalazinamine 2566-(4-chlorophenyl)-4-ethyl-N- 484 C1 0.012 0.003 0.049(4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)- 3-pyridazinamine257 4-phenyl-N-(4-(7H-purin-6- 432 B3 0.868 0.129 1.200 yloxy)phenyl)-1-phthalazinamine 258 4-(3-(dimethylamino)phenyl)- 515 A1 0.005 0.0020.004 N-(4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 259 4-(4-chlorophenyl)-N-(4-((2- 594 C1 0.023 0.0060.051 (4- morpholinylcarbonyl)thieno[3, 2-b]pyridin-7-yl)oxy)phenyl)-1-phthalazinamine 34 4-(4,5-dimethyl-1,3-thiazol-2- 507 B3 0.013 0.0100.062 yl)-N-(4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 260 4-(4,5-dimethyl-2-thienyl)-N- 506 B3 0.008 0.0090.002 (4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 261 N-(4-((7-(methyloxy)-1,5- 504 A1 1.605 0.156 1.200naphthyridin-4-yl)oxy)phenyl)- 4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1-phthalazinamine 262 N-(4-((7-(methyloxy)-1,5- 534.2 A1 0.1020.006 1.200 naphthyridin-4-yl)oxy)phenyl)-4-(4-(methylsulfinyl)phenyl)-1- phthalazinamine 263N-(4-((7-(methyloxy)-1,5- 550 A1 0.036 0.002 0.138naphthyridin-4-yl)oxy)phenyl)- 4-(4-(methylsulfonyl)phenyl)-1-phthalazinamine 264 N-(4-((6-(4-morpholinyl)-4- 526 D1 0.139 0.0160.387 quinolinyl)oxy)phenyl)-4- phenyl-1-phthalazinamine 2658-((4-((4-(4-chlorophenyl)-1- 501 D2 0.113 0.009 0.056phthalazinyl)amino)phenyl)oxy)- 1,5-naphthyridine-3- carbonitrile 2664-(4-chlorophenyl)-N-(4-(9H- 466 B3 0.679 0.045 1.200purin-6-yloxy)phenyl)-1- phthalazinamine 2674-(4-chlorophenyl)-N-(6-((2- 562 C5 0.011 0.000 0.013(1-methyl-1H-imidazol-5- yl)thieno[3,2-b]pyridin-7-yl)oxy)-3-pyridinyl)-1- phthalazinamine 268 N-(4-((7-(methyloxy)-1,5-487 A1 0.064 0.003 0.066 naphthyridin-4-yl)oxy)phenyl)-4-(6-methyl-3-pyridinyl)-1- phthalazinamine 269 N-(4-((6-(methyloxy)-4-491 B3 0.049 0.006 0.016 quinolinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1- phthalazinamine 270 7-((4-((4-(4-chlorophenyl)-1-580 C1 0.084 0.010 0.082 phthalazinyl)amino)phenyl)oxy)-N,N-diethylthieno[3,2- b]pyridine-2-carboxamide 271 N-(4-(7-methoxy-1,5-508 B3 0.066 0.024 0.004 naphthyridin-4-ylthio)phenyl)-4-(4-methylthiophen-2- yl)phthalazin-1-amine 2724-(2,3-dihydrobenzofuran-5- 489.1 A1 0.033 0.001 0.006yl)-N-(4-(thieno[3,2-b]pyridin- 7-yloxy)phenyl)phthalazin-1- amine 273N-(4-(7H-pyrrolo[2,3- 431 B3 1.660 0.039 1.200d]pyrimidin-4-yloxy)phenyl)-4- phenylphthalazin-1-amine 2744-ethyl-N-(4-(7-methoxy-1,5- 466 B4 0.066 0.004 0.029naphthyridin-4-ylthio)phenyl)- 6-phenylpyridazin-3-amine 2756-(4-chlorophenyl)-4-ethyl-N- 485 C1 0.156 0.011 0.161(6-(7-methoxy-1,5- naphthyridin-4-yloxy)pyridin- 3-yl)pyridazin-3-amine276 N-(4-(5,7-difluoroquinolin-4- 477.1 B3 0.670 0.018 0.054yloxy)phenyl)-4- phenylphthalazin-1-amine 2774-((4-((4-(4,5-dimethyl-1,3- 501 B3 0.065 0.007 0.035 thiazol-2-yl)-1-phthalazinyl)amino)phenyl)oxy)- 7-quinolinecarbonitrile 2784-(5-chloro-2-pyridinyl)-N-(4- 506 B3 0.082 0.004 0.011((6-(methyloxy)-4- quinolinyl)oxy)phenyl)-1- phthalazinamine 2794-(1,3-benzodioxol-5-yl)-N-(4- 491 A1 0.078 0.001 0.011(thieno[3,2-b]pyridin-7- yloxy)phenyl)-1- phthalazinamine 280N-(4-((7-(methyloxy)-1,5- 512.2 A1 0.062 0.002 0.080naphthyridin-4-yl)oxy)phenyl)- 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1-phthalazinamine 281 4,5-dimethyl-N-(4-((7- 450 C2 0.696 0.0190.378 (methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)-6-phenyl-3-pyridazinamine 33 4-(4-chlorophenyl)-N-(4-(1,5- 492 B2 0.022 0.003 0.002naphthyridin-4-ylthio)phenyl)- 1-phthalazinamine 282N-(4-((6,7-bis(methyloxy)-4- 536 C1 25.000 0.189 1.200cinnolinyl)oxy)phenyl)-4-(4- chlorophenyl)-1- phthalazinamine 2834-(2-chloro-4-pyridinyl)-N-(4- 507.2 A1 0.100 0.010 0.343((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)- 1-phthalazinamine284 4-(4-chlorophenyl)-N-(3- 524 B3 0.019 0.007 0.011fluoro-4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 285 N-(4-(1,5-naphthyridin-4- 458 B2 0.029 0.002 0.009ylthio)phenyl)-4-phenyl-1- phthalazinamine 2864-(4-chlorophenyl)-N-(4-((2- 563 B3 0.087 0.022 0.088(3-methyl-1,2,4-oxadiazol-5- yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-1- phthalazinamine 287 4-(4-ethynylphenyl)-N-(4-((7- 4960.061 0.013 0.060 (methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)-1-phthalazinamine 288 N-(4-((2-(3-methyl-1,2,4- 529 B3 0.302 0.039 0.828oxadiazol-5-yl)thieno[3,2- b]pyridin-7-yl)oxy)phenyl)-4-phenyl-1-phthalazinamine 289 4-(4-methyl-2-thienyl)-N-(4- 467 B3 0.0680.011 0.073 (thieno[3,2-b]pyridin-7- yloxy)phenyl)-1- phthalazinamine290 4-(4-chlorophenyl)-N-(4-(7H- 465 B3 0.350 0.009 0.397pyrrolo[2,3-d]pyrimidin-4- yloxy)phenyl)-1- phthalazinamine 2914-(2,2-difluoro-1,3- 552 A1 0.031 0.010 0.045benzodioxol-5-yl)-N-(4-((7- (methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1- phthalazinamine 292 N-(4-((6-(methyloxy)-4- 487 B30.144 0.011 0.012 quinolinyl)thio)phenyl)-4- phenyl-1-phthalazinamine293 4-(2,2-difluoro-1,3- 527 A1 0.266 0.006 0.045benzodioxol-5-yl)-N-(4- (thieno[3,2-b]pyridin-7- yloxy)phenyl)-1-phthalazinamine 45 N-(4-((6-(1-methyl-1H- 521 D3 0.079 0.030 0.056pyrazol-4-yl)-4- quinolinyl)oxy)phenyl)-4- phenyl-1-phthalazinamine 43N-(4-((4-((4-phenyl-1- 498 D1 0.112 0.008 0.025phthalazinyl)amino)phenyl)oxy)- 6-quinolinyl)acetamide 2944-phenyl-N-(4-(4- 457 B3 +++ +++ +++ quinolinylthio)phenyl)-1-phthalazinamine 295 N-(4-((5,7-difluoro-4- 493 B2 25.000 +++ +++quinolinyl)thio)phenyl)-4- phenyl-1-phthalazinamine 296(7-(4-(4-(4-methylthiophen-2- 594 C1 +++ +++ +++ yl)phthalazin-1-ylamino)phenylthio)thieno[3,2- b]pyridin-2- yl)(morpholino)methanone 2974-(4-chlorophenyl)-N-(4-(6- 522 B3 0.036 0.031 0.014 methoxyquinolin-4-ylthio)phenyl)phthalazin-1- amine 298 4-(4-chloro-2-thienyl)-N-(4- 513B3 0.014 0.023 0.027 ((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 299 N-(4-((7-(methyloxy)-1,5- 486 B3 0.018 0.015 0.033naphthyridin-4-yl)oxy)phenyl)- 4-(3-methylphenyl)-1- phthalazinamine 54N-(4-((7-(methyloxy)-4- 469 0.176 0.020 0.028quinolinyl)methyl)phenyl)-4- phenyl-1-phthalazinamine 3004-ethyl-N-(4-((7-(methyloxy)- 511 B4 0.112 0.067 0.1201,5-naphthyridin-4- yl)oxy)phenyl)-6-((4aR,8aS)- octahydro-2(1H)-isoquinolinyl)-3- pyridazinamine 301 N-(4-((7-bromo-1,5- 570 B3 0.0350.063 0.029 naphthyridin-4-yl)thio)phenyl)- 4-(4-chlorophenyl)-1-phthalazinamine 302 4-(4-chlorophenyl)-N-(4-((2- 580 B3(3-methyl-1,2,4-oxadiazol-5- yl)thieno[3,2-b]pyridin-7-yl)thio)phenyl)-1- phthalazinamine 303 N-(4-((2-(3-methyl-1,2,4- 545 B325.000 0.070 0.250 oxadiazol-5-yl)thieno[3,2-b]pyridin-7-yl)thio)phenyl)-4- phenyl-1-phthalazinamine 3044-(5-chloro-2-pyridinyl)-N-(4- 523 B3 0.013 0.019 0.008((7-(methyloxy)-1,5- naphthyridin-4-yl)thio)phenyl)- 1-phthalazinamine305 N-(4-((7-(methyloxy)-1,5- 486 B3 naphthyridin-4-yl)oxy)phenyl)-4-(4-methylphenyl)-1- phthalazinamine 306 4-(1,3-benzodioxol-5-yl)-N-(4-516.1 A1 0.011 0.030 0.006 ((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)- 1-phthalazinamine 3074-ethyl-N-(4-((7-(methyloxy)- 464 C1 0.022 0.006 0.0231,5-naphthyridin-4- yl)oxy)phenyl)-6-(4- methylphenyl)-3- pyridazinamine308 4-(4-chlorophenyl)-N-(4-(1,5- 492 B3 0.029 0.004 0.006naphthyridin-4-ylthio)phenyl)- 1-phthalazinamine 309N-(4-(1,5-naphthyridin-4- 458 B3 0.054 0.003 0.021ylthio)phenyl)-4-phenyl-1- phthalazinamine 310 4-phenyl-N-(4-(4- 457 B30.209 0.017 0.011 quinolinylthio)phenyl)-1- phthalazinamine 311N-(4-((5,7-difluoro-4- 493 B2 25.000 0.093 0.055quinolinyl)thio)phenyl)-4- phenyl-1-phthalazinamine 312(7-(4-(4-(4-methylthiophen-2- 596 B3 0.022 0.030 0.032 yl)phthalazin-1-ylamino)phenylthio)thieno[3,2- b]pyridin-2- yl)(morpholino)methanone 313morpholino(7-(4-(4- 576 B3 0.091 0.056 0.076 phenylphthalazin-1-ylamino)phenylthio)thieno[3,2- b]pyridin-2-yl)methanone 314 (7-(4-(4-(4-610 B3 0.058 0.057 0.030 chlorophenyl)phthalazin-1-ylamino)phenylthio)thieno[3,2- b]pyridin-2- yl)(morpholino)methanone 3154-(4-chlorophenyl)-N-(4-(6- 521 B3 0.036 0.031 0.014 methoxyquinolin-4-ylthio)phenyl)phthalazin-1- amine 316 4-(4-chloro-2-thienyl)-N-(4- 512B3 0.014 0.023 0.027 ((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 317 N-(4-((7-(methyloxy)-1,5- 486 A1 0.018 0.015 0.033naphthyridin-4-yl)oxy)phenyl)- 4-(3-methylphenyl)-1- phthalazinamine 318N-(4-((2-(3-methyl-1,2,4- 545 B3 25.000 0.070 0.250oxadiazol-5-yl)thieno[3,2- b]pyridin-7-yl)thio)phenyl)-4-phenyl-1-phthalazinamine 319 N-(4-((7-(methyloxy)-4- 469.2 unique 0.1760.020 0.028 quinolinyl)methyl)phenyl)-4- phenyl-1-phthalazinamine 3204-ethyl-N-(4-((7-(methyloxy)- 511 B4 0.112 0.067 0.1201,5-naphthyridin-4- yl)oxy)phenyl)-6-((4aR,8aS)- octahydro-2(1H)-isoquinolinyl)-3- pyridazinamine 321 4-ethyl-N-(4-((7-(methyloxy)- 457B4 0.304 0.051 1.200 1,5-naphthyridin-4- yl)oxy)phenyl)-6-(1-piperidinyl)-3-pyridazinamine 322 4-ethyl-N-(4-((7-(methyloxy)- 480 B40.033 0.032 0.017 1,5-naphthyridin-4- yl)thio)phenyl)-6-(4-methylphenyl)-3- pyridazinamine 323 4-(4-chlorophenyl)-N-(4-((2- 579.1B3 25.000 25.000 0.131 (3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridin-7- yl)thio)phenyl)-1- phthalazinamine 324N-(4-((7-bromo-1,5- 570 B3 0.035 0.063 0.029naphthyridin-4-yl)thio)phenyl)- 4-(4-chlorophenyl)-1- phthalazinamine325 4-(5-chloro-2-pyridinyl)-N-(4- 523 B3 0.013 0.019 0.008((7-(methyloxy)-1,5- naphthyridin-4-yl)thio)phenyl)- 1-phthalazinamine326 N-(4-((6-(methyloxy)-7- 577 C2 0.026 0.039 0.060((phenylmethyl)oxy)-4- quinolinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine 327 4-(6-(methyloxy)-2-pyridinyl)- 488 B3 0.1180.014 0.017 N-(4-(4-quinolinylthio)phenyl)- 1-phthalazinamine 3284-(4-chlorophenyl)-N-(4-((7- 503.2 unique 0.047 0.032 0.006(methyloxy)-4- quinolinyl)methyl)phenyl)-1- phthalazinamine 3294-phenyl-N-(4-(1H- 446 B3 0.114 0.009 0.057 pyrrolo[2,3-b]pyridin-4-ylthio)phenyl)-1- phthalazinamine 330 4-(4-chlorophenyl)-N-(4-(1H- 480B3 0.038 0.009 0.016 pyrrolo[2,3-b]pyridin-4- ylthio)phenyl)-1-phthalazinamine 331 N-(4-((7-(methyloxy)-4- 487 B3 0.192 0.155 0.021quinolinyl)thio)phenyl)-4- phenyl-1-phthalazinamine 3324-(4-chlorophenyl)-N-(4- 497 B3 0.016 0.003 0.001(thieno[3,2-b]pyridin-7- ylthio)phenyl)-1- phthalazinamine 3334-(4-chlorophenyl)-N-(4- 491 B3 25.000 0.036 1.200 (quinolin-4-ylthio)phenyl)phthalazin-1- amine 334 4-(4-chlorophenyl)-N-(4-(7- 521 B30.049 0.067 0.018 methoxyquinolin-4- ylthio)phenyl)phthalazin-1- amine335 6-(3-chlorophenyl)-4-ethyl-N- 484 C1 0.062 0.021 0.191(4-(7-methoxy-1,5- naphthyridin-4- yloxy)phenyl)pyridazin-3- amine 336N-(4-(1,5-naphthyridin-4- 478 B2 0.019 0.010 0.001 ylthio)phenyl)-4-(4-methylthiophen-2- yl)phthalazin-1-amine 337 N-(4-(7-methoxy-1,5- 497.1B3 0.076 0.015 0.229 naphthyridin-4-yloxy)phenyl)-4-thiomorpholinophthalazin-1- amine 338 N-(4-(7-(1-methyl-1H-pyrazol-5212 D3 0.005 0.009 0.005 4-yl)quinolin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine 339 4-phenyl-N-(4-(7-(thiophen-3- 523.1 D30.021 0.028 0.027 yl)quinolin-4- yloxy)phenyl)phthalazin-1- amine 340N-(4-((1H-benzo[d]imidazol-1- 428 B3 25.000 25.000 1.200yl)methyl)phenyl)-4- phenylphthalazin-1-amine 341N-(4-((1H-benzo[d]imidazol-1- 462 B3 25.000 25.000 1.200yl)methyl)phenyl)-4-(4- chlorophenyl)phthalazin-1- amine 3424-(4-chlorophenyl)-N-(4-(5,7- 527 B2 0.189 0.045 0.044difluoroquinolin-4- ylthio)phenyl)phthalazin-1- amine 343N-(4-(7-(furan-3-yl)quinolin-4- 507.2 D3 0.024 0.008 0.025yloxy)phenyl)-4- phenylphthalazin-1-amine 344 N-(4-(7-(5-methylfuran-2-521.2 D3 0.057 0.022 0.044 yl)quinolin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine 345 4-(4-chlorophenyl)-N-(4-(7- 505 B2 0.0400.024 0.013 methoxyquinolin-4- yloxy)phenyl)phthalazin-1- amine 346N-(4-(7-methoxy-1,5- 495 B1 0.044 0.024 0.016naphthyridin-4-ylthio)phenyl)- 4-(piperidin-1-yl)phthalazin-1- amine 347N-(4-(6-methoxy-1,5- 472 C2 0.067 0.010 0.039naphthyridin-4-yloxy)phenyl)- 4-phenylphthalazin-1-amine 3484-(4-chlorophenyl)-N-(4-(6- 522 B2 0.057 0.023 0.012methoxy-1,5-naphthyridin-4- ylthio)phenyl)phthalazin-1- amine 3494-(4-chlorophenyl)-N-(4-((2,3- 479.2 25.000 0.045 1.200dihydrobenzo[b][1,4]oxazin-4- yl)methyl)phenyl)phthalazin-1- amine 350N-(4-(7-methoxy-1,5- 477 A2 0.040 0.007 0.077naphthyridin-4-yloxy)phenyl)- 4-(3-methylisoxazol-5-yl)phthalazin-1-amine 351 7-(4-(4-(4- 522.0, B3 0.008 0.003 0.053chlorophenyl)phthalazin-1- 524.0 ylamino)phenylthio)thieno[3,2-b]pyridine-2-carbonitrile 352 N-(4-(1H-pyrazolo[3,4- 447.1 B3 0.0740.001 0.055 b]pyridin-4-ylthio)phenyl)-4- phenylphthalazin-1-amine 353N-(4-(7-methoxy-1,6- 488 B3 0.058 0.008 0.007naphthyridin-4-ylthio)phenyl)- 4-phenylphthalazin-1-amine 3544-(4-chlorophenyl)-N-(4-(7- 522 B3 0.025 0.009 0.007methoxy-1,6-naphthyridin-4- ylthio)phenyl)phthalazin-1- amine 3554-phenyl-N-(4-(thieno[3,2- 463 B3 0.241 0.006 0.015 b]pyridin-7-ylthio)phenyl)phthalazin-1- amine 356 4-(4-fluorophenyl)-N-(4-(7- 506 A10.036 0.012 0.007 methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1- amine 357 N-(4-(7-methoxy-1,5- 518 A1 0.0290.012 0.007 naphthyridin-4-ylthio)phenyl)- 4-(4-methoxyphenyl)phthalazin-1- amine 358 N-(4-(1,5-naphthyridin-4- 450 B40.049 0.006 0.035 ylthio)phenyl)-4-ethyl-6-p- tolylpyridazin-3-amine 359N-(4-(1H-pyrazolo[3,4- 481.1 B3 0.012 0.017 0.013b]pyridin-4-ylthio)phenyl)-4-(4- chlorophenyl)phthalazin-1- amine 3604-(4-(4-(4- 498.1 B3 25.000 0.345 0.413 chlorophenyl)phthalazin-1-ylamino)phenylthio)-N- methylpicolinamide 361 4-(4-(4-(4- 482 B3 0.2450.173 0.220 chlorophenyl)phthalazin-1- ylamino)phenoxy)-N-methylpicolinamide 362 N-(4-(3H-imidazo[4,5- 447 B3 0.066 0.092 0.105b]pyridin-7-ylthio)phenyl)-4- phenylphthalazin-1-amine 363N-(4-(3H-imidazo[4,5- 481 B3 0.019 0.036 0.032b]pyridin-7-ylthio)phenyl)-4-(4- chlorophenyl)phthalazin-1- amine 3644-(5-chloropyridin-2-yl)-N-(4- 522 B3 0.036 0.073 0.005(7-methoxyquinolin-4- ylthio)phenyl)phthalazin-1- amine 3654-(5-chloropyridin-2-yl)-N-(4- 492 B3 0.016 0.011 0.003 (quinolin-4-ylthio)phenyl)phthalazin-1- amine 366 4-(4-methylthiophen-2-yl)-N- 483B3 0.037 0.051 0.002 (4-(thieno[3,2-b]pyridin-7-ylthio)phenyl)phthalazin-1- amine 367 N-(4-(7-methoxy-1,5- 462.1 C10.028 0.057 0.039 naphthyridin-4-yloxy)phenyl)- 4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyridazin-1- amine 368 N-(4-(7-methoxyquinolin-4- 461.2 C10.040 0.063 0.021 yloxy)phenyl)-4-phenyl-6,7- dihydro-5H-cyclopenta[d]pyridazin-1- amine 369 N-(4-(6-bromocinnolin-4- 556 C125.000 3.003 >1.200000 yloxy)phenyl)-4-(4- chlorophenyl)phthalazin-1-amine 370 4-phenyl-N-(4-(pyrazolo[1,5- 431.2 B3 0.505 0.594 0.757a]pyrimidin-7- yloxy)phenyl)phthalazin-1- amine

EXAMPLE 371

Synthesis of 4-chloro-5,7-dimethoxyquinoline Step 1:5-((3,5-Dimethoxyphenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

In a dried 2-necked round bottom flask equipped with reflux condenserand inert atmosphere, 2,2-dimethyl-1,3-dioxane-4,6-dione (5.3 g, 37mmol) was dissolved in triethyl orthoformate (37 ml, 221 mmol) and themixture was stirred at 100° C. under nitrogen for 1.5 h.3,5-dimethoxybenzenamine (5.6 g, 37 mmol) was added and heatingcontinued for 4.5 h. The reaction mixture was cooled down to RT andpoured into hexane (50 mL). The solid was filtered off and washed withhexane to afford5-((3,5-dimethoxyphenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dioneas a light yellow solid. MS: W/z=[M+H]⁺. 308.1 Calc'd for C₁₅H₁₇NO₆:307.3.

Step 2: 5,7-Dimethoxyquinolin-4-ol

A solution of5-((3,5-dimethoxyphenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione(9.23 g, 30.0 mmol) in diphenyl ether was heated at 200° C. for 20 min.It was cooled down to RT. Hexane was added and the mixture was stirredat RT for 30 mins. The solvent was removed to furnish5,7-dimethoxyquinolin-4-ol as a light brown solid, which was used fornext step without further purification. MS: m/z=[M+H]⁺. 206.2 Calc'd forC₁₁H₁₁NO₃: 205.2.

Step 3: 4-Chloro-5,7-dimethoxyquinoline

To a mixture of crude 5,7-dimethoxyquinolin-4-ol (5.36 g, 26 mmol) andHunig'sBase (9.1 ml, 52 mmol) in toluene, was added POCl₃(29 ml, 313mmol). The mixture was refluxed for 5 h. Excess POCl₃ was removed underreduced pressure and the mixture was azeotroped with toluene. Theresultant gum was treated with sat. NaHCO₃ until no gas generated. Themixture was extracted with EtOAc, the organic extracts were combined andwashed with sodium bicarbonate and solvent removed under reducedpressure. The crude product was purified via column chromatography onsilica gel (RediSep 120 g column, gradient elution with 0-50% EtOAc/DCM)to afford 4-chloro-5,7-dimethoxyquinoline as a yellow solid. MS:m/z=[M+H]⁺. 224.2 Calc'd for C₁₁H₁₀ClN: 223.7.

EXAMPLE 372

Synthesis of 4-Chloro-6(trifluoromethoxy)quinoline Step 1:2,2-Dimethyl-5-((4-(trifluoromethoxy)phenylamino)methylene)-1,3-dioxane-4,6-dione

In a 48 mL sealed tube was dissolved 2,2-dimethyl-1,3-dioxane-4,6-dione(0.81 g, 5.6 mmol) in trimethyl orthoformate (5.6 mL). The mixture washeated to 100° C. and stirred for 2 h. To the mixture was added4-(trifluoromethoxy)aniline (0.76 mL, 5.6 mmol) and it was stirred at100° C. for 3 hours. The reaction was cooled to RT, diluted with hexane,filtered, and the filtered solids were air dried to yield2,2-dimethyl-5-((4-(trifluoromethoxy)phenylamino)methylene)-1,3-dioxane-4,6-dioneas a light yellow solid. MS [M+H]=332.0; Calc'd 331.2 for C₁₄H₁₂F₃NO₅.

Step 2: 6-(Trifluoromethoxy)quinolin-4(1H)-one

In a 50 mL round bottom flask with a reflux condenser attached wasdissolved2,2-dimethyl-5-((4-(trifluoromethoxy)phenylamino)methylene)-1,3-dioxane-4,6-dione(1.00 g, 3.02 mmol) in Ph2O (8.63 mL, 0.35 M). The mixture was heated to250° C. in a heating mantle. At about 180° C., the reaction turned froma light yellow and homogeneous to an orange, then to a dark brown colorand began to bubble, slowly at first and then more violently. Internaltemperature of reaction went up to 230° C., although heating ceased at180° C. Heating at 250° C. while stirring was continued for fiveminutes, and the reaction was cooled to RT, diluted with hexane, and theprecipitate was filtered to yield 6-(trifluoromethoxy)quinolin-4(1H)-oneas a crude brown solid. MS [M+H]=230.1; Calc'd 229.2 for C₁₀H₆F₃NO₂.

Step 3: 4-Chloro-6-(trifluoromethoxy)quinoline

In a 25 mL round bottom flask was dissolved6-(trifluoromethoxy)quinolin-4(1H)-one (0.50 g, 2.18 mmol) in POCl₃(3.05mL). A reflux condenser was attached and the reaction mixture wasstirred at 130° C. for 3 hours. The reaction turned dark brown andbecame homogeneous. The reaction was cooled to RT, poured slowly intoice bath while stirring. A thick gum resulted, which was basified with6N NaOH to give a dark brown solution. The solution was extracted intoethyl acetate, washed 1× water, 1× NaCl, dried with Na2SO4, filteredthrough fritted funnel, concentrated down. The curde material waspurified using an Isco silica gel chromatography system eluting with asolvent gradient of 0-100% CH₂Cl₂:MeOH(90:10)/CH₂Cl₂. The productfractions were concentrated down to yield4-chloro-6-(trifluoromethoxy)quinoline as an orange oil. MS [M+H]=248.0;Calc'd 247.6 for C₁₀H₅ClF₃NO.

EXAMPLE 373

Synthesis of 7-Chloro-2-methylthieno[3,2-b]pyridine

A solution of n-butyllithium (0.71 ml, 1.77 mmol) in THF (20.0 mL) wascooled to −78° C. and 7-chlorothieno[3,2-b]pyridine (200 mg, 1.18 mmol)was added dropwise. The mixture stirred at −78° C. for 1 h to afford ayellow suspension. A solution of iodomethane (0.22 ml, 3.54 mmol) in THF(1.0 mL) was added dropwise via syringe, and the mixture stirred at −78°C. for 3 h.; LCMS showed completion of the reaction. The reaction wasquenched with water and warmed to RT. The layers were separated, and theaqueous phase was extracted with DCM. The combined organic phases werewashed with brine, dried over anhydrous sodium sulfate, filtered, andconcentrated to afford a tan solid. This material was purified viacolumn chromatography (RediSep 40 g column, gradient elution with 10-50%ethyl acetate-hexane) to afford 7-chloro-2-methylthieno[3,2-b]pyridineas white solid. MS [M+H]=184.1; Calc'd for C₈H₆ClNS: 183.7.

EXAMPLE 374

Synthesis of 4-Chloro-6-methoxyquinazoline Step 1:6-Methoxnquinazolin-4(3H)-one

Formamidine acetate (12.5 g, 119.6 mmol) was added to a stirred solutionof 2-amino-5-methoxybenzoic acid (2.0 g, 119.6 mmol) in methoxy ethanol(40 mL) at RT. The reaction mixture was stirred at 140° C. (T oil bath)for ˜17 h. LC/MS showed completion of the reaction. The reaction cooledto RT and concentrated in vacuo. Aq. NaHCO₃ solution was added to theconcentrate and the precipitated solids were filtered (rinsing withwater) to afford 6-methoxyquinazolin-4(3H)-one as off-white solid. MS[M+H]=177.1; Calc'd for C₉H₈N₂O₂: 176.2.

Step 2: 4-Chloro-6-methoxyquinazoline

A pressure resistant bottle was charged with6-methoxyquinazolin-4(3H)-one (1.0 g, 5.68 mmol) and POCl₃(17.5 ml,187.3 mmol). The resulting mixture was heated at 105° C. for 18 hours.The reaction mixture was cooled to RT and poured onto ice slurry whilestirring heavily. The solution was quickly neutralized with 6N NaOH, andproduct extracted with DCM. The organic layer was collected, dried oversodium sulfate and concentrated to afford 4-chloro-6-methoxyquinazolineas tan solid. MS: [M+H]=194.9; Calc'd for C₉H₇ClN₂O: 194.6.

EXAMPLE 375

Synthesis of 4-Chloroquinoline-6-carbonitrile

A pyrex reaction tube was charged with Pd(PPh₃)₄(200 mg, 173 μmol),4-chloro-6-iodoquinoline (1.00 g, 3454 μmol), zinc cyanide (406 mg, 3454μmol) and DMF. The tube was purged with argon, sealed, and theheterogeneous mixture was stirred at 50° C. for 17 h. The mixture waspoured into water and the resulting solids were filtered, washed withwater, and dried. The crude material was purified by silica gelchromatography, 0-5% MeOH/DCM to provide4-chloroquinoline-6-carbonitrile as a white solid. MS: [M+H]=189.

EXAMPLE 376

Synthesis of 8-Chloro-2,3-dimethoxy-1,5-naphthyridine Step 1:2,3-Dimethoxy-5-nitropyridine

A round bottom flask was charged with methanol under nitrogen. Freshlycut sodium (91 mg, 3977 μmol) was added, and the mixture was stirred atRT under nitrogen until the sodium had dissolved.2-Chloro-3-methoxy-5-nitropyridine (500 mg, 2652 μmol) was added and thereaction mixture was stirred under nitrogen at RT. After ˜15 min themixture became heterogeneous and thick, and GC/MS analysis of a sampletaken at 0.5 h indicated complete conversion to the desired product. Themixture was diluted with DCM and water and the layers were separated.The aqueous portion was extracted with additional DCM and the combinedorganics were dried, filtered and concentrated. The crude solid waspassed through a silica plug using 5% MeOH/DCM. The filtrate wasconcentrated to provide 2,3-dimethoxy-5-nitropyridine as a light yellowsolid. MS [M+H]=185.

Step 2: 2,3-Dimethoxy-5-nitropyridine

A stainless steel bomb was charged with 2,3-dimethoxy-5-nitropyridine(430 mg, 2335 μmol), 10% Pd/C (124 mg, 1168 μmol) and 4.7 mL EtOAc. Thevessel was sealed and was purged with hydrogen once, before filling withhydrogen at a pressure of 2 attn. The reaction mixture was heated at 50°C. for 3 h. Upon cooling, the mixture was filtered through a pad ofCelite, rinsing with EtOAc. The filtrate was concentrated and passedthrough a silica plug using 5% MeOH/DCM. The filtrate was concentratedto provide 5,6-dimethoxypyridin-3-amine as a peach colored oil thatcrystallized upon standing. GC/MS confirmed the correct mass to be[M+H]=155.

Step 3:(E)-5-((5,6-dimethoxapyridin-3-ylimino)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

A round bottom flask was charged with 2-methoxyacetaldehyde dimethylacetal (2076 μl, 2076 μmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (299mg, 2076 μmol). The flask was fitted with a reflux condenser and themixture was heated at 100° C. for 2 h under nitrogen.5,6-Dimethoxypyridin-3-amine (320 mg, 2076 μmol) was added, and within aminute a solid had precipitated out of solution. The heterogeneousmixture was heated at 100° C. for 10 min. The mixture was cooled to RTand the solids were filtered and washed with hexanes.(E)-5-((5,6-dimethoxypyridin-3-ylimino)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dionewas isolated as a yellow/orange solid. MS [M+H]=309.

Step 4: 6,7-dimethoxy-1,5-naphthyridin-4(1H)-one

A round bottom flask was charged with(E)-5-((5,6-dimethoxypyridin-3-ylimino)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione(450 mg, 1460 μmol) and 4.2 mL diphenyl ether. A reflux condenser wasattached, and the solution was heated at 200° C. for 0.5 h. Uponcooling, hexane was added and the solids were filtered and washed withhexane. 6,7-dimethoxy-1,5-naphthyridin-4(1H)-one was isolated as a tansolid. MS [M+H]=207

Step 5: 8-chloro-2,3-dimethoxy-1,5-naphthynidine

A pyrex reaction tube was charged with6,7-dimethoxy-1,5-naphthyridin-4(1H)-one (1.80 g, 8729 μmol) phosphorusoxychloride (8137 μl, 87295 μmol). The tube was sealed and the mixturewas heated at 110° C. for 2 h. Upon cooling the mixture was poured ontoice and brought to pH 10 with dropwise addition of 6N NaOH. The aqueousportion was extracted with EtOAc three times. The extracts werecombined, dried with MgSO₄, filtered and concentrated. The solids weretriturated in hexane, filtered and dried to provide8-chloro-2,3-dimethoxy-1,5-naphthyridine as a white solid. MS [M+H]=225.

EXAMPLE 377

Synthesis of4(1-(2-methoxyethyl)-1H-pyrrolo[3,2-b]pyridin-7-ylthio)benzenamine Step1: 1-(2-methoxyethyl)-7-(4-nitrophenylthio)-1H-pyrrolo[3,2-b]pyridine

A sealed vial was charged with potassium hydroxide (0.124 g, 2.21 mmol)and DMSO (5 mL). 7-(4-nitrophenylthio)-1H-pyrrolo[3,2-b]pyridine (0.150g, 0.553 mmol) was added and the reaction was stirred for 45 minutes.1-Bromo-2-methoxyethane (0.104 ml, 1.11 mmol) was added, the system wasflushed with argon, and the reaction was stirred at RT for 2 hours.LC-MS indicated starting material remaining, so 1 eq. bromoether wasadded and the reaction stirred for two more hours. The reaction wasdiluted with water and extracted four times with DCM and twice withethyl acetate. The combined organic layers were dried with sodiumsulfate, filtered, and concentrated. The material was purified viacolumn chromatography (gradient elution 0-5% MeOH:DCM) to afford1-(2-methoxyethyl)-7-(4-nitrophenylthio)-1H-pyrrolo[3,2-b]pyridine as anorange oil that solidified under high vacuum. MS: M+H+=330.1

Step 2:4-(1-(2-methoxyethyl)-1H-pyrrolo[3,2-b]pyridin-7-ylthio)benzenamine

A sealed vial was charged with1-(2-methoxyethyl)-7-(4-nitrophenylthio)-1H-pyrrolo[3,2-b]pyridine(0.147 g, 0.446 mmol) and methanol (5 mL). Tin (II) chloride dihydrate(0.504 g, 2.23 mmol) was added and the reaction was stirred at 50° C.for 3 hours. The reaction was concentrated and dissolved in DCM. Thesolution was washed with saturated sodium bicarbonate solution, whichwas extracted with DCM. The combined organic layers were washed withwater, dried with sodium sulfate, filtered, and concentrated. Thematerial was purified via column chromatography (gradient elution 0-10%DCM:MeOH) to afford4-(1-(2-methoxyethyl)-1H-pyrrolo[3,2-b]pyridin-7-ylthio)benzenamine asan orange oil that solidified under high vacuum. MS: M+H+=300.1.

EXAMPLE 378

Synthesis of2-(3,4-bis(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneStep 1: 4-Bromo-1,2-bis(2-methoxyethoxy)benzene

Potassium hydroxide (4.45 g, 79.4 mmol) was dissolved in DMSO (40 mL)and stirred for five minutes. 4-Bromobenzene-1,2-diol (3.00 g, 15.9mmol) was added and the reaction was stirred for 45 minutes.1-Bromo-2-methoxyethane (5.97 ml, 63.5 mmol) was added and the reactionstirred at RT for 18 hours. The reaction was diluted with water andextracted twice with ethyl acetate. The combined organic layers weredried with sodium sulfate, filtered, and concentrated. The material waspurified via column chromatography (gradient elution 0-50% EtOAc:Hex) toafford 4-bromo-1,2-bis(2-methoxyethoxy)benzene as a clear oil. MS:M+H+=305.1.

Step 2:2-(3,4-Bis(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A sealed tube was charged with 4-bromo-1,2-bis(2-methoxyethoxy)benzene(1.00 g, 3.28 mmol), bis(pinacolato)diboron (1.25 g, 4.92 mmol),potassium acetate (0.965 g, 9.83 mmol), and dioxane (10 mL).1,1′-Bis(diphenylphosphino)ferrocene-palladium dichloride (0.240 g,0.328 mmol) was added, the system was flushed with argon, and the tubewas sealed. The reaction was stirred at 100° C. overnight. The reactionwas filtered through celite and washed with DCM until solvent passingthrough was clear. The filtrate was concentrated, dissolved in hexanesand passed through a membrane filter. The filtrate was concentrated toafford2-(3,4-bis(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneas a brown oil. MS: M+H+=353.2.

EXAMPLE 379

Synthesis of2-(2-(2-Methoxyethoxy)ethoxy)-8-(4-nitrophenylthio)-1,5-naphthyridineand1-(2-(2-Methoxyethoxy)ethyl)-8-(4-nitrophenylthio)-1,5-naphthyridin-2(1H)-one

8-(4-Nitrophenylthio)-1,5-naphthyridin-2(1H)-one (0.099 g, 0.33 mmol)and potassium carbonate (0.091 g, 0.66 mmol) were dissolved in ACN (5mL) and stirred for 5 minutes. 1-Bromo-2-(2-methoxyethoxy)ethane (0.18ml, 1.3 mmol) was added and the reaction was stirred overnight at 60° C.The reaction was cooled to RT, filtered, concentrated, dissolved inethyl acetate, and washed with sat. sodium bicarbonate solution. Theorganic layer was dried with sodium sulfate, filtered, and concentratedto afford a mixture of2-(2-(2-methoxyethoxy)ethoxy)-8-(4-nitrophenylthio)-1,5-naphthyridineand1-(2-(2-methoxyethoxy)ethyl)-8-(4-nitrophenylthio)-1,5-naphthyridin-2(H1H)-oneas a dark brown oil. MS: M+H+=402.2.

EXAMPLE 380

Synthesis of 4-aminophenyl)(7-methoxyquinolin-4-yl)methanone Step 1:7-Methoxy-4-(phenalthio)quinoline

A resealable tube under N₂ was charged with 4-chloro-7-methoxyquinoline(1.00 g, 5.16 mmol), thiophenol (0.528 ml, 5.16 mmol), cesium carbonate(2.52 g, 7.75 mmol) and DMSO (5 mL). The mixture was heated at 100° C.for 2 hrs. The crude reaction mixture was directly purified by silicagel chromatography using 0-10% CH₂Cl₂:MeOH to afford7-methoxy-4-(phenylthio)quinoline as a off-white solid. MS: M+H+=268.0.

Step 2: 7-Methoxy-4-(phenylsulfinyl)quinoline

To 7-methoxy-4-(phenylthio)quinoline (1.38 g, 5.16 mmol) in CH₂Cl₂(50mL) at −78° C. was added m-CPBA (77%) (1.25 g, 7.23 mmol) portionwise.The mixture was allowed to slowly warm to RT (3 hrs). The reactionmixture was diluted with CH₂Cl₂ then neutralized with NaHCO₃(sat.). Theaqueous phase was extracted three times with DCM then the organic layerwas dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudemixture was purified by silica gel chromatography using 0-10%CH₂Cl₂:MeOH to afford 7-methoxy-4-(phenylsulfinyl)quinoline as aoff-white foam. MS: M+H+=284.0.

Step 3: (7-Methoxyquinolin-4-yl)(4-nitrophenyl)methanol

To a solution of 7-methoxy-4-(phenylsulfinyl)quinoline (0.232 g, 0.819mmol) in THF (6 mL) at −78° C. was added phenylmagnesium chloride (2.0 Min THF) (0.819 ml, 1.64 mmol). After 5 min, the solution was warmed toRT for 15 minutes. The solution was then cooled to −78° C. and4-nitrobenzaldehyde (0.371 g, 2.46 mmol) was added in one portion. After5 min, the solution was warmed to RT. After 1 hr at RT, the reaction wasquenched with saturated NH₄Cl. The mixture was diluted with CH₂Cl₂ andwashed with water and brine. The organic fraction was dried with Na₂SO₄and concentrated in vacuo. The yellow residue was purified by silica gelchromatography using 20-100% Hexanes:EtOAc to afford(7-methoxyquinolin-4-yl)(4-nitrophenyl)methanol as a white solid. MS:M+H+=311.2.

Step 4: (7-Methoxyquinolin-4-yl)(4-nitrophenyl)methanone

A mixture of (7-methoxyquinolin-4-yl)(4-nitrophenyl)methanol (220 mg,0.709 mmol) and manganese dioxide (247 mg, 2.84 mmol) in CHCl₃(20 mL)was heated to 50° C. After 3 hrs, the mixture was cooled to RT andfiltered over a silica plug to afford(7-methoxyquinolin-4-yl)(4-nitrophenyl)methanone as a yellow solid thatwas advanced without further purification. MS: M+H+=309.1.

Step 5: (4-aminophenyl)(7-methoxyquinolin-4-yl)methanone

A mixture of (7-methoxyquinolin-4-yl)(4-nitrophenyl)methanone (55 mg,0.18 mmol) and palladium on carbon, 10% (57 mg, 0.54 mmol) in EtOAc (5mL) and MeOH (0.5 mL) at RT was exposed to an atmosphere of Hydrogen(balloon). After 2 hrs, crude LCMS showed complete conversion to(4-aminophenyl)(7-methoxyquinolin-4-yl)methanone with a trace amount ofcorresponding alcohol. The material was filtered through a plug ofcelite, concentrated in vacuo, and advanced without furtherpurification. MS: M+H+=279.1.

EXAMPLE 381

Synthesis of (4-aminophenyl)(7-methoxyquinolin-4-yl)methanol

A mixture of (7-methoxyquinolin-4-yl)(4-nitrophenyl)methanone (96 mg,0.31 mmol) and palladium on carbon, 10% (99 mg, 0.93 mmol) in EtOAc (6mL) and MeOH (2 mL) at RT was exposed to an atmosphere of hydrogen(balloon). Crude LCMS after 8 hrs showed complete conversion to(4-aminophenyl)(7-methoxyquinolin-4-yl)methanol with trace amounts ofthe corresponding keto-aniline. The material was filtered through a plugof celite and concentrated in vacuo to afford crude(4-aminophenyl)(7-methoxyquinolin-4-yl)methanol as a white foam that wasadvanced without further purification. MS: M+H+=281.1.

EXAMPLE 382

Synthesis of 4-(1-(7-methoxyquinolin-4-yl)ethyl)benzenamine Step 1:7-Methoxy-4-(1-(4-nitrophenyl)vinyl)quinoline

To a mixture of methyltriphenylphosphonium chloride (0.54 g, 1.7 mmol)in THF (10 mL) at −78° C. was added n-butyllithium, 2.5 M in hexanes(0.80 ml, 2.0 mmol). After 20 min, a mixture of(7-methoxyquinolin-4-yl)(4-nitrophenyl)methanone (0.177 g, 0.57 mmol) inTHF (5 mL) was slowly added. After 10 min, the mixture was allowed towarm to RT. The reaction was quenched with saturated aqueous NH₄Cl. Themixture was diluted with EtOAc and washed with water and brine. Afterdrying the organic fraction with Na₂SO₄, the solvent was removed invacuo and the residue purified by silica gel chromatography using40-100% hexanes:EtOAc to afford7-methoxy-4-(1-(4-nitrophenyl)vinyl)quinoline as a yellow foam. MS:M+H+=307.1.

Step 2: 4-(1-(7-Methoxyquinolin-4-yl)ethyl)benzenamine

A mixture of 7-methoxy-4-(1-(4-nitrophenyl)vinyl)quinoline (0.146 g,0.477 mmol) and Palladium on carbon, 10% (0.152 g, 1.43 mmol) in EtOAc(10 mL) and MeOH (1 mL) at RT was exposed to an atmosphere of Hydrogen(balloon). After 3 hrs, the mixture was filtered through celite andconcentrated in vacuo to afford4-(1-(7-methoxyquinolin-4-yl)ethyl)benzenamine as a white foam.MH+=279.1.

EXAMPLE 383

Synthesis of 5,6,7,8-Tetrahydroimidazo[1,2-a]pyrazine Step 1:Imidazo[1,2-a]pyrazine

A round bottom set up with reflux condenser was charged withpyrazin-2-amine (1000 mg, 10.52 mmol), 2-chloroacetaldehyde (˜50% wt)(2.03 ml, 31.55 mmol), and EtOH (23 mL) and heated under refluxovernight. Next day LC/MS showed completion. The mixture wasconcentrated and passed through a plug of silica (solvent used: 1%MeOH/DCM) to afford imidazo[1,2-a]pyrazine as off-white solid. MS[M+H]=120.1; Calc'd for C₆H₅N₃: 119.1

Step 2: 5,6,7,8-Tetrahydroimidazo[1,2-a]pyrazine

Imidazo[1,2-a]pyrazine (250 mg, 2.1 mmol) and palladium on carbon (10%)(55.8 mg, 0.53 mmol) were placed in a pressure resistant bottle andsuspended under nitrogen in 0.5M HCl/EtOH. The mixture was stirred underat 45 psi H₂ for 16 hrs. LC/MS showed completion. The next day, thereaction mixture was passed through celite cake. The filtrate wasconcentrated under reduced pressure to afford a tan solid. This was useddirectly without further purification. MS: [N+H]=124.2; Calc'd forC₆H₉N₃: 123.2.

EXAMPLE 384

Synthesis of (7R)-7-Fluoro-octahydropyrrolo[1,2-a]pyrazine Step 1:(2S,4R)- and (2R,4R) 4-Fluoropyrrolidine-2-methyl ester

A round bottom flask was charged with(2S,4R)-4-fluoropyrrolidine-2-carboxylic acid (300 mg, 2254 μmol) and 22mL MeOH. The heterogeneous mixture was cooled to 0° C. under nitrogen,and thionyl chloride (181 μl, 2479 μmol) was added dropwise. Thereaction mixture was allowed to warm slowly to RT, and stirring wascontinued overnight at 65° C. The mixture was concentrated under highvacuum to provide methyl 4-fluoropyrrolidine-2-carboxylate hydrochlorideas a mixture of the (2S,4R) and (2R,4R) diastereomers, confirmed by ¹Hand ¹³C NMR.

Step 2: (2S,4R)- and (2R,4R)-Methyl1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)acetyl)-4-fluoropyrrolidine-2-carboxylate

A pyrex reaction tube was charged with (2S,4R), (2R,4R)-methyl4-fluoropyrrolidine-2-carboxylate hydrochloride (350 mg, 1906 μmol),1H-benzo[d][1,2,3]triazol-1-ol (309 mg, 2287 μmol),2-(((9H-fluoren-9-yl)methoxy)carbonyl)acetic acid (567 mg, 1906 μmol),N-ethyl-N-isopropylpropan-2-amine (996 μL, 5719 μmol) and 7.6 mL DMF.The mixture was stirred for 5 min at RT, andbenzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (1012 mg, 2287 μmol) was added, and the mixture wasstirred at RT overnight. The mixture was diluted with DCM and washedwith water. The organic portion was dried with MgSO₄, filtered,concentrated, and then was concentrated twice from toluene to removeDMF. The crude oil was purified by silica gel chromatography DCM to 5%MeOH/DCM to provide (2S,4R), (2R,4R)-methyl1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)acetyl)-4-fluoropyrrolidine-2-carboxylateas a waxy solid. MS: [M+H]=427.

Step 3: (7R)-7-Fluoro-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione

A scintillation vial was charged with (2S,4R), (2R,4R)-methyl1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)acetyl)-4-fluoropyrrolidine-2-carboxylate(815 mg, 1911 μmol), 19 mL MeOH and piperidine (946 μl, 9556 μmol). Themixture was stirred at RT overnight The mixture was concentrated,dissolved in DCM/MeOH and purified by silica gel chromatography, 50-100%90/10/1 DCM/MeOH/NH₄OH in DCM.(7R)-7-fluoro-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione was isolated asa white solid, and confirmed by ¹H-NMR.

Step 4: (7R)-7-Fluoro-octahydropyrrolo[1,2-a]pyrazine

A pressure bottle was charged with(7R)-7-fluoro-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (200 mg, 1162μmol) and 4.6 mL THF, and the bottle was purged with nitrogen and cooledto 0° C. Lithium aluminum hydride (2323 μl, 2323 μmol) was added. Themixture was allowed to warm to RT, and was then heated at reflux for 4h. The reaction was cooled to 0° C. and 1 mL water was added carefully,followed by 1 mL 6N NaOH. The mixture was stirred for 15 min, and wasfiltered through a pad of Celite, washing with EtOAc. The filtrate wasconcentrated and a sample was analyzed by H-NMR and GC/MS: [M+H]=145.

EXAMPLE 385

Synthesis of 7,7-Difluoro-octahydropyrrolo[1,2-a]pyrazine Step 1:(R)-1-Tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate

A pyrex reaction tube was charged with (R)-1-tert-butyl 2-methyl4-oxopyrrolidine-1,2-dicarboxylate (750 mg, 3083 μmol) and 12.3 mL DCM,and the solution was cooled to 0° C. under nitrogen. DAST (1018 μl, 7708μmol) was added dropwise, and the mixture was allowed to warm to RT. Thereaction was quenched after 3 h by careful addition of saturated NaHCO₃.After 5 min, the layers were separated, the aqueous was extracted withDCM, and the combined organics were dried, filtered and concentrated.The crude oil was purified by silica gel chromatography, 10-50%EtOAc/hex, to provide (R)-1-tert-butyl 2-methyl4,4-difluoropyrrolidine-1,2-dicarboxylate as a yellow oil. Mass wasconfirmed by GC/MS: [M+H]=266.

Step 2: Crude (S)-methyl-4,4-difluoronyrrolidine-2-carboxylate TFA salt

A round-bottom flask was charged with (R)-1-tert-butyl 2-methyl4,4-difluoropyrrolidine-1,2-dicarboxylate (675 mg, 2545 μmol), 10.2 mLDCM and trifluoroacetic acid (980 μl, 12724 μmol). The mixture wasstirred at RT. After 6 h, TLC (50% hex/EtOAc, KMnO4 stain) indicatedcomplete conversion. The mixture was concentrated, and the crude(S)-methyl-4,4-difluoropyrrolidine-2-carboxylate TFA salt was use as is.

Step 3: (R)-Methyl1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)acetyl)-4,4-difluoropyrrolidine-2-carboxylate

A round bottom flask was charged with Fmoc-glycine (756 mg, 2543 μmol),1H-benzo[d][1,2,3]triazol-1-ol (412 mg, 3052 μmol),(S)-methyl-4,4-difluoropyrrolidine-2-carboxylate TFA salt (710 mg, 2543μmol), Hunig'sBase (2221 μl, 12717 μmol) and 10.2 mL DMF. The mixturewas stirred for 5 min at RT, andbenzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (1350 mg, 3052 μmol) was added. The reaction mixturewas stirred overnight at RT. The solution was diluted with DCM andwashed with water. The organic layer was dried, filtered, andconcentrated. The crude oil was purified by silica gel chromatography,0-5% MeOH/DCM to provide (R)-methyl1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)acetyl)-4,4-difluoropyrrolidine-2-carboxylate.MS: [M+H]=445.

Step 4: (S)-7,7-Difluoro-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione

A round bottom flask was charged with (R)-methyl1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)acetyl)-4,4-difluoropyrrolidine-2-carboxylate(1.10 g, 2475 μmol) and 25 mL MeOH. Piperidine (1225 μl, 12375 μmol) wasadded, and the mixture was stirred at RT overnight. The mixture wasconcentrated and purified by silica gel chromatography, DCM in 90/10DCM/MeOH to provide(S)-7,7-difluoro-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione as a whitesolid. GC/MS: [M+H]=191.

Step 5: 7,7-Difluoro-octahydropyrrolo[1,2-a]pyrazine

A pressure bottle was charged with(S)-7,7-difluoro-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (350 mg, 1841μmol) and THF under nitrogen, and the solution was cooled to 0° C. undernitrogen. Lithium aluminum hydride (3681 μl, 3681 μmol) was added, themixture was allowed to warm to RT, followed by heating at reflux for 3h. 2 mL of water was carefully added, followed by 2 mL of 6N NaOH. Afterstirring for 10 min, the mixture was filtered through Celite and washedwith EtOAc. The filtrate was concentrated. GC/MS: [M+H]=163.

EXAMPLE 386

Synthesis of 4(4-Phenylnaphthalen-1-ylamino)phenol Step 1:4-phenylnaphthalen-1-amine

A pressure bottle was charged with 4-bromonaphthalen-1-amine (500 mg,2251 μmol), phenylboronic acid (357 mg, 2927 μmol), PdCl₂(dppf)-CH₂Cl₂adduct (91.9 mg, 113 μmol), 2.0 M sodium carbonate (2251 μl, 4503 μmol)and 9.0 mL of dioxane. The bottle was sealed and the mixture was heatedat 85° C. for 2 h. LCMS showed desired product as the major component.The mixture was diluted with DCM and washed with water. The organicportion was dried, filtered and concentrated. The crude material waspurified by silica gel chromatography, DCM to 2% MeOH/DCM to provide4-phenylnaphthalen-1-amine. MS: [M+H]=220.

Step 2: N-(4-methoxyphenyl)-4-phenylnaphthalen-1-amine

A pyrex reaction tube was charged with sodium tert-butoxide (239 mg,2490 μmol), Pd2(dba)₃(81.4 mg, 88.9 μmol), S-Phos (146 mg, 356 μmol),1-bromo-4-methoxybenzene (333 mg, 1779 μmol), 4-phenylnaphthalen-1-amine(390 mg, 1779 μmol) and dioxane. The tube was sealed and the mixture wasstirred at 100° C. for 2 h. LCMS showed complete conversion to product.The mixture was diluted with DCM and washed with water. The organicportion was dried, filtered and concentrated. The crude material waspassed through a plug of silica gel using 50% EtOAc/hex and the filtratewas concentrated to provide the desired product. MS: [M+H]=326.

Step 3: 4-(4-phenylnaphthalen-1-ylamino)phenol

A round bottom flask was charged withN-(4-methoxyphenyl)-4-phenylnaphthalen-1-amine (600 mg, 1844 μmol) and 6mL 1:1 HBr (100 μl, 1844 μmol) and HOAc (106 μl, 1844 μmol). The flaskwas fitted with a reflux condenser and the mixture was heated at 140° C.After 1 h, LCMS showed ˜50% conversion to desired product. Heating wascontinued for another 5 h. Upon cooling, the mixture was brought toneutral pH by addition of 6 N NaOH and extracted with DCM. The organicportion was dried, filtered and concentrated. The crude material waspurified by silica gel chromatography, 0-50% EtOAc/hex to provide4-(4-phenylnaphthalen-1-ylamino)phenol. MS: [M+H]=312.

EXAMPLE 387

Synthesis of N-(4(7-(difluoromethoxy)-1,5-naphthyridin-4-ylthio)phenylsphenylphthalazin-1-amine Step 1:8-(4-(4-phenylphthalazin-1-ylamino)phenylthio)-1,5-naphthyridin-3-ol

A reaction vial was charged withN-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-phenylphthalazin-1-amine(40 mg, 82 μmol), HBr (891 μl, 16408 μmol), and acetic acid (939 μl,16408 μmol). The vial was sealed, and the reaction mixture was stirredat 85° C. for 2 hrs. Upon cooling, LC/MS analysis showed a mass ion peakcorresponding toN-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-phenylphthalazin-1-amine(40 mg, 82 μmol). The reaction mixture was poured into an ice-cooledaqueous solution of sodium bicarbonate. Extraction of the product wasattempted with DCM. However, the product seemed insoluble in DCM and waspresent in both the aqueous and organic layers, so all liquid wasremoved in vacuo. The resulting white solid was taken up in water andfiltered. The filtrate was washed several times with water, and theresulting yellow solid was analyzed by LCMS. LCMS analysis showed clean8-(4-(4-phenylphthalazin-1-ylamino)phenylthio)-1,5-naphthyridin-3-ol.The crude material was carried forward.

Step 2:N-(4-(7-(Difluoromethoxy)-1,5-naphthyridin-4-ylthio)phenyl)-4-phenylphthalazin-1-amine

DMF (338 μl, 84 μmol) and water (68 μl, 84 μmol) were added to a mixtureof cesium carbonate (39 mg, 118 μmol), sodium chlorodifluoroacetate (30mg, 194 μmol), and8-(4-(4-phenylphthalazin-1-ylamino)phenylthio)-1,5-naphthyridin-3-ol (40mg, 84 μmol) in a resealable tube. The tube was sealed and heated to100° C. for about 1.5 hrs, and then reaction progress was checked byLCMS. Conversion toN-(4-(7-(difluoromethoxy)-1,5-naphthyridin-4-ylthio)phenyl)-4-phenylphthalazin-1-aminewas low, so the reaction mixture was heated to 100° C. for an additional20 hours and again checked by LCMS. LCMS analysis showed mass peakcorresponding toN-(4-(7-(difluoromethoxy)-1,5-naphthyridin-4-ylthio)phenyl)-4-phenylphthalazin-1-amineas the major peak. The reaction mixture was diluted with water. A lighttan precipitate formed and was filtered through a 0.45 uM membranefilter. The precipitate was taken up in minimal DMSO and methanol andpurified by preparative HPLC{Gilson; 15-85% (0.1% TFA in CH₃CN) in H₂Oover 20 min}. Clean fractions were combined and neutralized withsaturated aqueous NaHCO₃ then extracted with ethyl acetate, dried overMgSO₄, filtered and concentrated to dryness in vacuo to afford pureN-(4-(7-(difluoromethoxy)-1,5-naphthyridin-4-ylthio)phenyl)-4-phenylphthalazin-1-amineas a white solid.

EXAMPLE 388

Synthesis of4-(4-(4-(4-Chlorophenyl)phthalazin-1-ylamino)phenylthio)quinolin-6-ol

A flask was charged with4-(4-chlorophenyl)-N-(4-(6-methoxyquinolin-4-ylthio)phenyl)phthalazin-1-amine(0.325 g, 0.624 mmol), AcOH (5.71 ml, 99.8 mmol) and HBr (5.42 ml, 99.8mmol). The mixture was stirred at 85° C. for 2 h, then cooled to RT andquenched with saturated aqueous NaHCO₃ to precipitate a solid. The solidwas filtered, washed with water and dried to give4-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenylthio)quinolin-6-ol asa light yellow solid. MS: m/z=[M+H]⁺. 508.0 Calc'd for C₂₉H₁₉ClN₄OS:507.0.

EXAMPLE 389

Synthesis of4-(4-Chlorophenyl)-N-(4-(6-(2-(2-methoxyethoxy)ethoxy)quinolin-4-ylthio)phenyl) phthalazin-1-amine

To a mixture of4-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenylthio)quinolin-6-ol(0.054 g, 0.11 mmol) and potassium carbonate (0.059 g, 0.43 mmol) in DMFwas added 1-bromo-2-(2-methoxyethoxy)ethane (0.057 ml, 0.43 mmol), theresulting mixture was stirred at 80° C. for 1 h. The crude product waspurified via column chromatography on silica gel (RediSep 40 g column,gradient elution with 0-60% (EtOAc-DCM) to afford4-(4-chlorophenyl)-N-(4-(6-(2-(2-methoxyethoxy)ethoxy)quinolin-4-ylthio)phenyl)phthalazin-1-amineas a light yellow solid. MS: m/z [M+H]⁺. 610.0 Calc'd for C₃₄H₂₉ClN₄O₃S:609.1.

EXAMPLE 390

Synthesis of4-(4-Chlorophenyl)-N-(4-(6-(2-(methylsulfonyl)ethoxy)quinolin-4-ylthio)phenyl) phthalazin-1-amine

To a solution of4-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenylthio)quinolin-6-ol(0.062 g, 0.12 mmol) in THF at 0° C., was added NaH (0.018 g, 0.73mmol). The mixture was stirred at 0° C. for 30 minutes.1-Chloro-2-(methylsulfonyl)ethane (0.035 g, 0.24 mmol) and trace amountof NaI were added. The mixture was stirred and warmed to RT for 15 h.The reaction was quenched with sat. NH₄Cl, and extracted with DCM. Thecombined organic layers were washed with brine, dried, filtered andconcentrated. The crude product was purified via column chromatographyon silica gel (RediSep 40 g column, gradient elution with 0-50% (90:10:1DCM/MeOH/NH₄OH-DCM) to afford4-(4-chlorophenyl)-N-(4-(6-(2-(methylsulfonyl)ethoxy)quinolin-4-ylthio)phenyl)phthalazin-1-amineas a light yellow solid. MS: m/z=[M+H]⁺. 614.0 Calc'd forC₃₂H₂₅ClN₄O₃S₂: 613.1.

EXAMPLE 391

Synthesis of4-(5-Chloropyridin-2-yl)-N-(4-(furo[3,2-b]pyridin-7-ylthio)phenyl)phthalazin-1-amine

A resealable tube was charged with1-chloro-4-(5-chloropyridin-2-yl)phthalazine (0.095 g, 0.34 mmol),4-(2-(trimethylsilyl)furo[3,2-b]pyridin-7-ylthio)benzenamine (0.090 g,0.29 mmol) and 2-butanol (3.0 mL). The system was flushed with argon,and the tube was sealed. The mixture stirred at 100° C. for 2 h. LC-MSshowed starting aniline and hydrolyzed phthalazine, so 90 mg ofchlorophthalazine was added and the reaction was stirred for 1 h at 100°C. The reaction was concentrated, re-dissolved in THF, and TBAF (1.0 Min THF) (0.29 ml, 0.29 mmol) was added. The reaction was stirred at 60°C. overnight. The reaction was concentrated and purified via Gilson HPLC(gradient elution 10-90% MeCN:H₂O). The clean fractions were partitionedbetween DCM and saturated sodium bicarbonate solution and the layerswere separated. The aqueous layer was extracted with DCM and thecombined organic layers were dried with sodium sulfate, filtered, andconcentrated to afford4-(5-chloropyridin-2-yl)-N-(4-(furo[3,2-b]pyridin-7-ylthio)phenyl)phthalazin-1-amineas a yellow solid. MS: M+H+=482.1.

EXAMPLE 392

Synthesis of7-Methoxy-4-(4-(4-phenylphthalazin-1-ylamino)phenoxy)quinoline-6-carbonitrile

7-Methoxy-4-(4-(4-phenylphthalazin-1-ylamino)phenoxy)quinoline-6-carboxamide(125 mg, 243 μmol) and thionyl chloride (10 ml, 24341 μmol) werecombined and heated to 80° C. for 3 hours. Thionyl chloride was thenremoved under vacuum. The mixture was then made basic with sat. sodiumbicarbonate and extracted with DCM. The organic extracts were combined,dried with sodium sulfate, filtered and concentrated. The product waspurified by silica gel chromatography using a 0 to 70% gradient of90/10/1 (DCM/methanol/ammonium hydroxide) in DCM. MS: M+H+=496.

EXAMPLE 393

Synthesis ofN-(4-(6-Methoxy-7-(2-methoxyethoxy)quinolin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine

6-Methoxy-4-(4-(4-phenylphthalazin-1-ylamino)phenoxy)quinolin-7-ol (45mg, 92 μmol) and cesium carbonate (33 mg, 102 μmol) were combined in DMF(2 Ml) and stirred for 5 min. 1-Bromo-2-methoxyethane (9.6 μl, 204 μmol)was added and the mixture was stirred at RT for 12 hours. DMF was thenremoved under vacuum overnight. The crude material was purified bysilica gel chromatography using 0 to 100% ethyl acetate in hexane toafford the titled product. MS: M+H+=545.

EXAMPLE 394

Synthesis of4-(4-Chloro-3-(2-(methylsulfonyl)ethoxy)phenyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amineStep 1: (2-(5-Bromo-2-chlorophenoxy)ethyl)(methyl)sulfane

5-Bromo-2-chlorophenol (500 mg, 2410 μmol) and(2-chloroethyl)(methyl)sulfane (262 μl, 2651 μmol) were combined withcesium carbonate (942 mg, 2892 μmol) in DMF and heated to 100° C. for 2h. The mixture was then filtered and purified using reverse phasechromatography. This purified material was carried forward to the nextstep.

Step 2:2-(4-Chloro-3-(2-(methylthio)ethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4,4,5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(79 mg, 313 μmol), (2-(5-bromo-2-chlorophenoxy)ethyl)(methyl)sulfane (80mg, 284 μmol), potassium acetate (84 mg, 852 μmol) and Pd(DPPF) werecombined in dioxane and stirred for 4 hours at 100° C. The mixture wasthen filtered, concentrated, and purified on silica using 0 to 40% ethylacetate in hexane. MS: M+Na⁺=351

Step 3:4-(4-Chloro-3-(2-(methylsulfonyl)ethoxy)phenyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine

4-(4-Chloro-3-(2-(methylthio)ethoxy)phenyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine(150 mg, 252 μmol) and oxone (464 mg, 755 μmol) were combined in 3:1MeOH/water (20 ml) and stirred for 3 h. The mixture was thenconcentrated to remove methanol, then extracted with DCM, dried withsat. sodium bicarb., and concentrated. The crude material was thenpurified by chromatography using 0 to 100% 90/10/1 in DCM, followed byreverse phase chromatography to provide the titled compound. MS:M+H+=628.

EXAMPLE 395

Synthesis ofN-(4-(7-Methoxy-1,5-naphthyridin-4-yloxy)phenyl)-4-(3-(2-methoxyethoxy)-4-methylphenyl)phthalazin-1-amine

5-(4-(4-(7-Methoxy-1,5-naphthyridin-4-yloxy)phenylamino)phthalazin-1-yl)-2-methylphenol(120 mg, 239 μmol) and cesium carbonate (234 mg, 718 μmol) were combinedin DMF and stirred for 5 min. 1-Bromo-2-methoxyethane (66.5 mg, 479μmol) was added and the mixture was stirred for 1 h. The mixture wasthen filtered and purified using reverse phase chromatography to providethe titled product. MS: M+H+=560.

EXAMPLE 396

Synthesis of4(4(4(7-Methoxy-1,5-naphthyridin-4-ylthio)phenylamino)phthalazin-1-yl)-1-methylpyridin-2(1H)-oneStep 1: 1-Methyl-4-(trimethylstannyl)pyridin-2(1H)-one

4-Iodo-1-methylpyridin-2(1H)-one (110 mg, 468 μmol),1,1,1,2,2,2-hexamethyldistannane (126 μl, 608 μmol), and the Pd catalystwere added to toluene and heated to 100° C. for 2 h. The mixture wasconcentrated and purified by silica gel chromatography using 0 to 30%MeOH in ethyl acetate.

Step 2:4-(4-(4-(7-Methoxy-1,5-naphthyridin-4-ylthio)phenylamino)phthalazin-1-yl)-1-methylpyridin-2(1H)-one

4-Chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine(148 mg, 331 μmol),1-methyl-4-(trimethylstannyl)pyridin-2(1H)-one (90mg, 331 μmol), and the Pd catalyst were added to toluene and heated to100° C. for 2 h. The mixture was concentrated and purified by silica gelchromatography using 0 to 30% MeOH in ethyl acetate. MS: M+H+=519.

EXAMPLE 397

Synthesis of5-Methoxy-N-(4(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)pyridazin-3-amine

A pyrex reaction tube was charged with potassium phosphate (88 mg, 415μmol), Pd₂dba₃ (16 mg, 17 mmol), Xantphos (22 mg, 38 mmol),4-(7-methoxy-1,5-naphthyridin-4-yloxy)benzenamine (92 mg, 346 μmol),3-chloro-5-methoxypyridazine (50 mg, 346 μmol), and toluene (1 mL). Thetube was purged with argon, sealed, and the mixture was heated at 100°C. for 4 h. LCMS showed complete conversion to desired product. Themixture was then concentrated and purified by silica gel chromatographyusing 0 to 60% (90/10/1 DCM/MeOH/ammonium hydroxide) in DCM. MS:M+H+=376.

EXAMPLE 398

Synthesis of4-(3-Fluoro-4-methylphenyl)-N-(4-(furo[3,2-b]pyridin-7-ylthio)phenyl)phthalazin-1-amine

A microwave vial was charged with 3-fluoro-4-methylphenylboronic acid(0.058 g, 0.38 mmol),4-chloro-N-(4-(2-(trimethylsilyl)furo[3,2-b]pyridin-7-ylthio)phenyl)phthalazin-1-amine(0.090 g, 0.19 mmol), and sodium carbonate (2.0 M in H₂O) (0.38 ml, 0.75mmol) and dissolved in toluene (1.5 mL) and water (0.2 mL).Pd(Ph3P)₄(0.011 g, 0.0094 mmol) was added and the reaction wasmicrowaved at 200° C. for 30 minutes. The reaction was partitionedbetween water and DCM. The layers were separated and the aqueous layerwas extracted twice with DCM. The combined organic layers were driedwith sodium sulfate, filtered, and concentrated. The material wasredissolved in 2 mL THF and TBAF (0.23 ml, 0.23 mmol) was added. Thereaction was stirred at RT overnight. The reaction was concentrated andpurified via Gilson HPLC (10-90% ACN:H₂O). The clean fractions werepartitioned between saturated sodium bicarbonate solution and DCM andthe aqueous layer was extracted with DCM. The combined organic layerswere dried with sodium sulfate, filtered, and concentrated to afford4-(3-fluoro-4-methylphenyl)-N-(4-(furo[3,2-b]pyridin-7-ylthio)phenyl)phthalazin-1-amineas a light yellow solid. MS: M+H+=479.1

EXAMPLE 399

Synthesis ofN-(4-(6-Aminoquinolin-4-ylthio)phenyl)-4-phenylphthalazin-1-amine

To a solution ofN-(4-(6-nitroquinolin-4-ylthio)phenyl)-4-phenylphthalazin-1-amine (228mg, 455 μmol) in 1 mL of DMF, was added tin (II) chloride (431 mg, 2273μmol) and 115 uL of water. After 15 minutes of sonication, the reactionwas stirred at rt. After 2 days, water was removed under vacuumazeotropically with benzene. DCM was added to the suspension. Yellowsolids precipitated out of the solution and were filtered off with DCM.The filtrate was concentrated and purified by RPLC on an acidic Gilsoncolumn system. Fractions containing the product were washed with sat.NaHCO₃. The product was extracted with DCM. The organic was washed withbrine, dried over MgSO₄, filtered, and concentrated. The product waspurified further by performing a column chromatography using 60:40DCM:(90:10:1 DCM:MeOH:NH₄OH). Yellow solid,N-(4-(6-aminoquinolin-4-ylthio)phenyl)-4-phenylphthalazin-1-amine wasobtained.

EXAMPLE 400

Synthesis ofS(4-((4-(4-Chlorophenyl)phthalazin-1-yl)(methyl)amino)phenoxy)-1,5-naphthyridin-2(1H)-oneStep 1:8-(4-(4-(4-Chlorophenyl)phthalazin-1-ylamino)phenoxy)-1,5-naphthyridin-2(1H)-one

In a 48 mL sealed pressure vessel, was added4-(4-chlorophenyl)-N-(4-(6-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine(0.280 g, 0.553 mmol), HBr (6.01 mL, 11.1 mmol), and acetic acid (6.34mL, 11.1 mmol). The mixture was stirred at 85° C. for 1 hour. Thereaction was monitored and found complete by LC/MS. The reaction mixturewas cooled to RT, carefully basified with 6 N NaOH. Light yellow solidscrashed out, which were filtered, rinsed with water and dried in vacuumoven to yield8-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenoxy)-1,5-naphthyridin-2(1H)-one.The product was used without further purification. MS:[M+H]=492.1;Calc'd 491.9 for C₂₈H₁₈ClN₅O₂

Step 2:8-(4-((4-(4-Chlorophenyl)phthalazin-1-yl)(methyl)amino)phenoxy)-1,5-naphthyridin-2(1H)-one

In a 20 mL sealed tube, was dissolved8-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenoxy)-1,5-naphthyridin-2(1H)-one(0.25 g, 0.508 mmol) in THF (2.2 mL), and the mixture was cooled to 0°C. Sodium Hydride, 60% in mineral oil (0.045 g, 1.12 mmol), was addedand the mixture was stirred at 0° C. for 1 hour. Iodomethane (0.070mL, 1. 12 mmol), was added and the mixture was warmed to 60° C., andstirred for 3 hours. A mixture of products was revealed by LC/MS. Themixture was cooled to RT, quenched with water, extracted into ethylacetate, washed 1× water, 1× NaCl, dried with Na₂SO₄, filtered throughfritted funnel, and filtrate was concentrated. The crude concentrate waspurified by reverse phase chromatography. The product containingfractions were extracted into DCM, washed 1× sodium carbonate, 1×H₂O,dried with Na₂SO₄, filtered through fritted funnel, and the filtrate wasconcentrated down to a light yellow solid containing two methylatedproducts. The solids were suspended in methanol, filtered, rinsed withmethanol, and air dried to yield8-(4-((4-(4-chlorophenyl)phthalazin-1-yl)(methyl)amino)phenoxy)-1,5-naphthyridin-2(1H)-one.MS: [M+H]=506.0; Calc'd 505.9 for C₂₉H₂₀ClN₅O₂.

EXAMPLE 401

Synthesis ofN-(4-(7-Methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-(1,2,3,6tetrahydropyridin-4-yl)phthalazin-1-amine Step 1: Tert-butyl4-(4-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenylamino)phthalazin-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate

In a 20 mL sealed tube, was added 1,4-dioxane (1.08 mL), purged thesolvent with nitrogen for 5 minutes, and sealed the tube. To the tubewas added4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine(0.150 g, 0.336 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.125 g, 0.404 mmol) and sodium carbonate (2.0 M aqueous) (0.336 mL,0.673 mmol). The mixture was purged with nitrogen, sealed, and then toit was added PdCl₂(dppf) (0.012 g, 0.017 mmol). The mixture was againpurged with nitrogen, sealed, and heated to 100° C., while stirring for3 hours. The reaction was cooled to RT and concentrated. The crudematerial was purified by Isco silica gel chromatography using 0-100%CH₂Cl₂:MeOH(90:110)/CH₂Cl₂. The product containing fractions wereconcentrated to yield tert-butyl4-(4-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenylamino)phthalazin-1-yl)-5,6-dihydropyridine-1(2H)-carboxylateas light yellow solid. MS: [M+H]=593.0; Calc'd 592.7 for C₃₃H₃₂N₆O₃S.

Step 2:N-(4-(7-Methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)phthalazin-1-amine

In a 20 mL sealed tube was dissolved tert-butyl4-(4-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenylamino)phthalazin-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.200 g, 0.337 mmol) in DCM (1.00 mL). To the mixture was added TFA(0.130 mL, 1.69 mmol). The mixture was stirred at 50° C. for 3 hours,then cooled to RT and concentrated. The crude material was purified onan Isco silica gel chromatography using 0-100% CH₂Cl₂:MeOH:NH₄OH(90:10:1)/CH₂Cl₂. The product fractions were concentrated to yieldN-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)phthalazin-1-amineas a light yellow solid. MS: [N+H]=493.0; Calc'd 492.6 for C₂₈H₂₄N₆OS.

EXAMPLE 402

Synthesis of4-Methoxy-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine

In a 100 ml RBF was added4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine(158 mg, 0.354 mmol) to a solution of sodium methoxide (96 mg, 1.772mmol) in MeOH. The mixture was heated to reflux with a water condenserattached. The solution was stirred for 16 hours. A white solidprecipitated. The mixture was cooled to 0° C., quenched with excessmethoxide, followed by saturated NH₄Cl, and the resulting solids werefiltered and washed with water. The crude solids were purified by GilsonReverse Phase HPLC eluting with a 15-70% gradient of ACN in water with0.1% TFA. The product fractions were combined, neutralized withsaturated sodium bicarbonate, extracted with 15 ml of methylene chloride(3×), dried organics over Na₂SO₄, filtered and concentrated filtrate invacuo to afford 4-methoxy-N-(4-(7-methoxy-1,5-naphthyridin-4ylthio)phenyl)phthalazin-1-amine as an off-white solid. MS: [M+H]=442.

EXAMPLE 403

Synthesis ofN-(4-(7-Methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-(2-(piperidin-2-yl)ethoxy)phthalazin-1-amine

Sodium Hydride (11 mg, 449 μmol), 2-(piperidin-2-yl)ethanol (58 mg, 449μmol), and benzene (2243 μl, 449 μmol) were combined in a resealabletube capped with a septum and heated to 40° C. for 30 minutes.4-Chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine(200 mg, 449 μmol) was added, and the reaction mixture was allowed tostir at 80° C. for 18 hours. The mixture was concentrated in vacuo andthe crude material was partitioned between methylene chloride and water.The organic layers were combined and over Na₂SO₄ and concentrated. Thecrude material was purified via ISCO, 12 g RediSep column eluting with a20-100% gradient of 90:10:1 (DCM:MeOH:NH₄OH) in DCM. The productfractions were combined and concentrated in vacuo to affordN-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-(2-(piperidin-2-yl)ethoxy)phthalazin-1-amine.MS: [M+H]=539.

EXAMPLE 404

Synthesis of4(4-(7-Methoxy-1,5-naphthyridin-4-ylthio)phenylamino)phthalazine-1-carbonitrile

In a 15 ml sealed pressure tube, was dissolved4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine(150 mg, 490 μmol) in 0.8 ml of DMSO. Sodium cyanide (72 mg, 1469 μmol)was added and the reaction was capped and stirred at 130° C. for 3hours. The reaction was cooled to RT and purified via Gilson ReversePhase HPLC eluting with a 12-75% gradient of ACN in water with 0.1% TFA.The product fractions were basified with saturated sodium bicarbonateand extracted into DCM. The DCM layers were dried over Na₂SO₄, filteredand concentrated in vacuo to afford4-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenylamino)phthalazine1-carbonitrile. MS: [M+H]=437.

EXAMPLE 405

Synthesis of8(4-(4-(5-Chloropyridin-2-yl)phthalazin-1-ylamino)phenylthio)-1,5-naphthyridin-2(1H)-one

A small reaction vial was charged with4-(5-chloropyridin-2-yl)-N-(4-(6-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine(50 mg, 0.096 mmol), HBr (1.04 mL, 19.12 mmol), and acetic acid (1.1 mL,19.12 mmol). The mixture was stirred at 85° C. for 2 hrs. LC/MS showedcompletion of the reaction. The reaction mixture was poured onto anaqueous sodium bicarbonate solution ice bath and the product wasextracted with DCM. The organic layer was dried over sodium sulfate andconcentrated to afford8-(4-(4-(5-chloropyridin-2-yl)phthalazin-1-ylamino)phenylthio)-1,5-naphthyridin-2(1H)-oneas yellow solid. MS: [M+H]=509.1; Calc'd for C₂₇H₁₇ClN₆OS: 509.

EXAMPLE 406

Synthesis of8(4(4-(4-Chlorophenyl)phthalazin-1-ylamino)phenylthio)-3-methoxy-1,5-naphthyridin-2(1H)-one

4-(4-Chlorophenyl)-N-(4-(6,7-dimethoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine(40 mg, 72 μmol) was added to a pyrex reaction tube along with 2 mL of1:1 HBr:AcOH. The tube was sealed and the mixture was heated at 85° C.for 1.5 h. Upon cooling the mixture was diluted with water and broughtto basic pH by dropwise addition of 6N NaOH. The solids were filtered,washed with water, and dried. The crude material was purified by silicagel chromatography, 10-50% 90/10/1 DCM/MeOH/NH₄OH in DCM to provide8-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenylthio)-3-methoxy-1,5-naphthyridin-2(1H)-oneas a light yellow solid. MS: [M+H]=539.

EXAMPLE 407

Synthesis of(5-(4-(4-(7-Methoxy-1,5-naphthyridin-4-yloxy)phenylamino)phthalazin-1-yl)thiophen-3-yl)methanol

A scintillation vial was charged with(5-(4-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenylamino)phthalazin-1-yl)thiophen-3-yl)methylacetate (137 mg, 249 μmol), 1.0 mL 3:1:1 THF:MeOH:water and lithiumhydroxide (47.8 mg, 1994 μmol). The homogeneous mixture was stirred atRT for 2 h. Water was added to the mixture, and the precipitated solidswere filtered, washed with water, and dried. The crude solids werepurified by reverse phase chromatography, Gilson, 10-90% 0.1% TFA/ACN inwater to provide(5-(4-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenylamino)phthalazin-1-yl)thiophen-3-yl)methanol.MS: [M+H]=508.

EXAMPLE 408

Synthesis of4-(4-(Fluoromethyl)thiophen-2-yl)N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine

A round bottom flask was charged with(5-(4-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenylamino)phthalazin-1-yl)thiophen-3-yl)methanol(71 mg, 140 μmol) and 2.8 mL DCM, and the mixture was cooled to 0° C.under nitrogen. (Diethylamino) trifluorosulfur (55 μl, 420 μmol) wasadded, and the mixture was stirred at 0° C. for 20 min and was thenallowed to warm to RT. After another 0.5 h, saturated NaHCO₃ was addedand the mixture was stirred for 10 min. The solids were filtered, andthe crude material was purified by silica gel chromatography, 90/10/1DCM/MeOH/NH₄OH in DCM, followed by reverse phase chromatography, Gilson,10-90% 0.1% TFA/ACN in water, to provide the titled compound. MS:[M+H]=510.

EXAMPLE 409

Synthesis ofS(4-(4-(4-Chlorophenyl)phthalazin-1-ylamino)phenoxy)-1,5-naphthyridin-3-olStep 1: 8-Chloro-1,5-naphthyridin-3-ol

A pressure-resistant vial was charged with8-chloro-3-methoxy-1,5-naphthyridine (1200 mg, 6166 mmol), borontribromide (6412 μl, 67825 μmol) and dichloroethane (10277 μl, 6166μmol). The vessel was sealed and the mixture was stirred at 60° C. for16 h. The reaction mixture was carefully diluted with DCM, and thesolids were filtered.The crude material was purified by silica gel chromatography with 40-70%(90:10:1 DCM/MeOH/NH₄OH)/DCM to afford 8-chloro-1,5-naphthyridin-3-ol.MS:[M+H]=181.

Step 2: 3-(Benzyloxy)-8-chloro-1,5-naphthyridine (220 mg, 813 μmol)

A pyrex reaction tube was charged with 8-chloro-1,5-naphthyridin-3-ol(165 mg, 914 μmol), potassium carbonate (631 mg, 4568 μmol),1-(chloromethyl)benzene (376 μl, 4568 μmol) and 3.7 mL DMF. The tube wassealed and the mixture was heated at 65° C. for 3 h. The reaction wasdiluted with DCM and washed with water. The organic portion was dried,filtered, and concentrated. The crude material was purified by silicagel chromatography, 0-25% EtOAc in DCM to provide product as a whitesolid. MS: [M+H]=271.

Step 3:N-(4-(7-(Benzyloxy)-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-chlorophenyl)phthalazin-1-amine

A pyrex reaction tube was charged with4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenol hydrochloride (344 mg,894 μmol), 3-(benzyloxy)-8-chloro-1,5-naphthyridine (220 mg, 813 μmol),cesium carbonate (662 mg, 2032 μmol) and 4.1 mL DMSO. The tube wassealed and the mixture was heated at 100° C. for 4 h. Water was addedand the resulting precipitate was filtered, washed with water and dried.The crude material was purified by silica gel chromatography, 90/10/1DCM/MeOH/NH₄OH in DCM to provideN-(4-(7-(benzyloxy)-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-chlorophenyl)phthalazin-1-amine.MS: [M+H]=583.

Step 4:8-(4-(4-(4-Chlorophenyl)phthalazin-1-ylamino)phenoxy)-1,5-naphthyridin-3-ol

A round bottom flask was charged withN-(4-(7-(benzyloxy)-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-chlorophenyl)phthalazin-1-amine(400 mg, 687 μmol), 10% Pd/C (73.1 mg, 687 μmol) and 3.4 mL MeOH. Theflask was fitted with a hydrogen-filled balloon and the mixture wasstirred overnight. The mixture was diluted with DCM and filtered throughCelite. The filtrate was concentrated and the crude material waspurified by reverse phase chromatography, Gilson, 10-90% 0.1% TFA/ACN inwater over 15 min to provide8-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenoxy)-1,5-naphthyridin-3-olas a light yellow solid. MS: [M+H]=492.

EXAMPLE 410

Synthesis of4-(4-fluorophenyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-ylsulfinyl)phenyl)phthalazin-1-amine

To a solution of4-(4-fluorophenyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine(29 mg, 0.057 mmol) in CH₂Cl₂(2 mL) and CHCl₃(3 mL) at −78° C. was addedmCPBA, 77% (14 mg, 0.080 mmol) in one portion. After 1 hr, the mixturewas slowly warmed to 0° C. and stirred for an additional 15 min. Thesolution was diluted with CH₂Cl₂ and washed with 10% Na₂S₂O₄ andsaturated aqueous NaHCO₃. After drying the organic fraction with Na₂SO₄,the solvent was removed in vacuo and the residue purified by silica gelchromatography using 100% CH₂Cl₂ to 8% MeOH:CH₂Cl₂ with 1% NH₄OH toafford4-(4-fluorophenyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-ylsulfinyl)phenyl)phthalazin-1-amine(18 mg, 60% yield) as a light yellow solid. MS: M+H+=522. 1.

The Examples disclosed in Table 2 below are additional representativeexamples, of the present invention. These Examples were made by themethods indicated in Table 2, which generally correlate to Methods A1-5,B1-5, C₁₋₅ and D1a, D1b, D2 and D3 of Examples 12-A, 12-B and 29-45herein. The MS data is the M+H⁺ ion value found for the example.Biological data is provided for a majority of those compoundsexemplified in Table 2. It should be understood and appreciated by thoseof ordinary skill in the art that where the data is missing for aparticular example, that data was unavailable. Also, data for certainexamples may not be completely accurate, as presented herein, likely dueto poor sample solubility, or other possible solution related issues,causing a decreased calculated activity. It is believed that theseexamples may be more active than recorded herein.

TABLE 2 MS 24h_4NPloidy dataMS AurA_IC50_IP AurB_IC50_IP EC50_IP Ex.Data (uM (uM (uM No Compound Name [M + H]+ Method Avg) Avg) Avg) 4114-(4-chlorophenyl)-N-(4-((7- 496.1 C1 >25.000000 >25.000000 >1.200000(methyloxy)-1,5-naphthyridin-4- yl)oxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine 412 4-(4-chlorophenyl)-N-(4-((7- 494.6C1 >25.000000 >25.000000 >1.200000 (methyloxy)-4-quinolinyl)oxy)phenyl)-6,7- dihydro-5H- cyclopenta[d]pyridazin-1-amine413 N-(6-((7-(methyloxy)-1,5- 489.1 B3 0.090 0.031 0.041naphthyridin-4-yl)thio)-3-pyridinyl)- 4-phenyl-1-phthalazinamine 4144-(4-chlorophenyl)-N-(6-((7- 522.5 B3 0.023 0.026 0.011(methyloxy)-1,5-naphthyridin-4- yl)thio)-3-pyridinyl)-1- phthalazinamine415 8-((4-((4-phenyl-1- 474 unique 0.043 0.012 0.015phthalazinyl)amino)phenyl)thio)- 1,5-naphthyridin-3-ol 387N-(4-((7-((difluoromethyl)oxy)-1,5- 524 unique 0.135 0.048 0.120naphthyridin-4-yl)thio)phenyl)-4- phenyl-1-phthalazinamine 4164-(3-amino-4-methylphenyl)-N-(4- 471.2 C2 0.098 0.003 0.008(1,5-naphthyridin-4-yloxy)phenyl)- 1-phthalazinamine 4174-phenyl-N-(4-((7-(1H-pyrazol-4- 507.2 D3 0.009 0.002 0.001yl)-4-quinolinyl)oxy)phenyl)-1- phthalazinamine 418N-(4-((6,7-bis(methyloxy)-4- 552 B3 0.028 0.012 0.004quinazolinyl)thio)phenyl)-4-(4- chlorophenyl)-1-phthalazinamine 419N-(4-((6-(methyloxy)-1,5- 502.8 B3 0.309 0.026 0.124naphthyridin-4-yl)thio)phenyl)-4- (6-methyl-2-pyridinyl)-1-phthalazinamine 420 N-(4-((7-(methyloxy)-1,5- 503.1 B3 0.072 0.015 0.029naphthyridin-4-yl)thio)phenyl)-4- (6-methyl-2-pyridinyl)-1-phthalazinamine 421 4-(6-methyl-2-pyridinyl)-N-(4-(1,5- 473.1 B3 0.1420.008 0.051 naphthyridin-4-ylthio)phenyl)-1- phthalazinamine 4226-(methyloxy)-4-((4-((4-phenyl-1- 487 C1 0.029 0.013 0.010phthalazinyl)amino)phenyl)oxy)-7- quinolinol 4234-(4-chlorophenyl)-N-(4-(1,6- 476.2 B3 0.047 0.003 0.031naphthyridin-4-yloxy)phenyl)-1- phthalazinamine 4244-(1,3-benzodioxol-5-yl)-N-(4-(1,6- 486.2 B3 0.055 0.004 0.024naphthyridin-4-yloxy)phenyl)-1- phthalazinamine 425N-(4-(1,6-naphthyridin-4- 458.2 B3 0.171 0.003 0.024ylthio)phenyl)-4-phenyl-1- phthalazinamine 4264-(4-chlorophenyl)-N-(4-(1,6- 492.1 B3 0.100 0.008 0.008naphthyridin-4-ylthio)phenyl)-1- phthalazinamine 4274-(1,3-benzodioxol-5-yl)-N-(4-(1,6- 502.1 B3 0.055 0.007 0.002naphthyridin-4-ylthio)phenyl)-1- phthalazinamine 4284-(4-methyl-2-thienyl)-N-(4-(1,6- 478.1 B3 0.032 0.013 0.016naphthyridin-4-ylthio)phenyl)-1- phthalazinamine 4294-(4-methyl-2-thienyl)-N-(4-(1,6- 462.1 B3 0.046 0.012 0.034naphthyridin-4-yloxy)phenyl)-1- phthalazinamine 4304-(5-chloro-2-pyridinyl)-N-(4-(1,6- 493.1 B3 0.084 0.007 0.007naphthyridin-4-ylthio)phenyl)-1- phthalazinamine 4314-(4-chlorophenyl)-N-(4-((7-((2- 565.1 B3 0.012 0.018 0.010(methyloxy)ethyl)oxy)-4- quinolinyl)thio)phenyl)-1- phthalazinamine 4324-(5-methyl-2-pyridinyl)-N-(4-(1,6- 457.1 B3 0.122 0.012 0.109naphthyridin-4-yloxy)phenyl)-1- phthalazinamine 4334-(5-methyl-2-pyridinyl)-N-(4-(1,6- 473.2 B3 0.056 0.004 0.017naphthyridin-4-ylthio)phenyl)-1- phthalazinamine 4344-(4-chlorophenyl)-N-(4-((6-((2- 565.2 B3 0.109 0.109 0.027(methyloxy)ethyl)oxy)-4- quinolinyl)thio)phenyl)-1- phthalazinamine 3884-((4-((4-(4-chlorophenyl)-1- 508 unique 0.020 0.003 0.013phthalazinyl)amino)phenyl)thio)-6- quinolinol 3894-(4-chlorophenyl)-N-(4-((6-((2- 610 C6 0.021 0.022 0.055 ((2-(methyloxy)ethyl)oxy)ethyl)oxy)-4- quinolinyl)thio)phenyl)-1-phthalazinamine 390 4-(4-chlorophenyl)-N-(4-((6-((2- 614C7 >125.000000 >125.000000 >1.200000 (methylsulfonyl)ethyl)oxy)-4-quinolinyl)thio)phenyl)-1- phthalazinamine 4354-(4-chlorophenyl)-N-(4-((5,7- 535 B3 0.038 0.121 0.009 dimethoxy-4-quinolinyl)oxy)phenyl)-1- phthalazinamine 4364-(4-chlorophenyl)-N-(4-((5,7- 551 B1 0.401 0.675 0.049 dimethoxy-4-quinolinyl)sulfanyl)phenyl)-1- phthalazinamine 4374-(4-chlorophenyl)-N-(4-((7-fluoro- 523 B3 0.042 0.035 0.0055-methoxy-4- quinolinyl)oxy)phenyl)-1- phthalazinamine 4384-(4-chlorophenyl)-N-(4-((7-fluoro- 539 B1 0.112 0.051 0.0165-methoxy-4- quinolinyl)sulfanyl)phenyl)-1- phthalazinamine 439N-(4-((5,7-dimethoxy-4- 537.1 B1 1.662 3.195 0.113quinolinyl)sulfanyl)phenyl)-4-(4- methyl-2-thiophenyl)-1-phthalazinamine 440 N-(4-((7-fluoro-5-methoxy-4- 525 B1 0.585 0.5960.029 quinolinyl)sulfanyl)phenyl)-4-(4- methyl-2-thiophenyl)-1-phthalazinamine 441 N-(4-((5,7-dimethoxy-4- 521.2 B3 0.456 0.135 0.008quinolinyl)oxy)phenyl)-4-(4- methyl-2-thiophenyl)-1- phthalazinamine 442N-(4-((7-fluoro-5-methoxy-4- 509.1 B3 0.157 0.017 <0.002300quinolinyl)oxy)phenyl)-4-(4- methyl-2-thiophenyl)-1- phthalazinamine 4434-(1,3-benzodioxol-5-yl)-N-(4-(1,5- 502 B2 0.012 0.002 0.007naphthyridin-4-ylthio)phenyl)-1- phthalazinamine 4444-(2,2-difluoro-1,3-benzodioxol-5- 539 A1 0.128 0.022 0.024yl)-N-(4-(1,5-naphthyridin-4- ylthio)phenyl)-1-phthalazinamine 4454-(2,3-dihydro-1-benzofuran-5-yl)- 500 A1 0.030 0.013 0.001N-(4-(1,5-naphthyridin-4- ylthio)phenyl)-1-phthalazinamine 4464-(1-benzofuran-5-yl)-N-(4-(1,5- 498 A1 0.035 0.011 0.000naphthyridin-4-ylthio)phenyl)-1- phthalazinamine 3927-(methyloxy)-4-((4-((4-phenyl-1- 496 unique 0.159 0.260 0.085phthalazinyl)amino)phenyl)oxy)-6- quinolinecarbonitrile 4474-(4-methyl-2-thienyl)-N-(4-(1,5- 462 B3 0.027 0.013 0.012naphthyridin-4-yloxy)phenyl)-1- phthalazinamine 4484-(4-chlorophenyl)-N-(4-(1,5- 476 B3 0.039 0.011 0.016naphthyridin-4-yloxy)phenyl)-1- phthalazinamine 393N-(4-((6-(methyloxy)-7-((2- 545 unique 0.013 0.017 0.001(methyloxy)ethyl)oxy)-4- quinolinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine 394 4-(4-chloro-3-((2- 628 unique 0.015 0.009 0.045(methylsulfonyl)ethyl)oxy)phenyl)- N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1- phthalazinamine 4495-(4-((4-((7-methoxy-1,5- 502 A1 0.026 0.006 <0.002300 naphthyridin-4-yl)oxy)phenyl)amino)-1- phthalazinyl)-2-methylphenol 3954-(3-(2-methoxyethoxy)-4- 560 unique 0.047 0.012 0.023methylphenyl)-N-(4-((7-methoxy- 1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 450 4-(4-chloro-3-(2- 596 unique 0.101 0.054 0.008methoxyethoxy)phenyl)-N-(4-((7- methoxy-1,5-naphthyridin-4-yl)sulfanyl)phenyl)-1- phthalazinamine 451 5-(4-((4-((7-methoxy-1,5- 518A1 0.078 0.033 <0.002300 naphthyridin-4- yl)sulfanyl)phenyl)amino)-1-phthalazinyl)-2-methylphenol 452 2-chloro-5-(4-((4-(1,5- 508 A1 0.0580.003 <0.002300 naphthyridin-4- ylsulfanyl)phenyl)amino)-1-phthalazinyl)phenol 453 4-(1H-indazol-6-yl)-N-(4-((7- 528 A1 0.028 0.032<0.002300 methoxy-1,5-naphthyridin-4- yl)sulfanyl)phenyl)-1-phthalazinamine 396 4-(4-((4-((7-methoxy-1,5- 519 unique0.050 >125.000000 0.008 naphthyridin-4- yl)sulfanyl)phenyl)amino)-1-phthalazinyl)-1-methyl-2(1H)- pyridinone 4544-(4-chlorophenyl)-N-(3,5-difluoro- 542 B3 0.050 0.010 0.0084-((7-methoxy-1,5-naphthyridin-4- yl)oxy)phenyl)-1-phthalazinamine 4554-(4-chlorophenyl)-N-(4-((7-fluoro- 493 C1 >125.000000 0.013 0.0084-quinolinyl)oxy)phenyl)-1- phthalazinamine 4565-methoxy-N-(4-((7-methoxy-1,5- 376 unique 1.003 0.058 >1.200000naphthyridin-4-yl)oxy)phenyl)-3- pyridazinamine 4577-((4-((4-(1,3-benzodioxol-5-yl)-1- 532 B3 0.062 0.015 0.021phthalazinyl)amino)phenyl)thio)thieno[3, 2-b]pyridine-2-carbonitrile 4587-((4-((4-phenyl-1- 488 B3 >25.000000 0.097 0.148phthalazinyl)amino)phenyl)thio)thieno[3, 2-b]pyridine-2-carbonitrile 4597-((4-((4-(4-methyl-2-thienyl)-1- 508 B3 0.210 0.150 0.048phthalazinyl)amino)phenyl)thio)thieno[3, 2-b]pyridine-2-carbonitrile 4607-((4-((4-(5-chloro-2-pyridinyl)-1- 523 B3 0.045 0.015 0.041phthalazinyl)amino)phenyl)thio)thieno[3, 2-b]pyridine-2-carbonitrile 4617-((4-((4-(6-methyl-3-pyridinyl)-1- 503 B3 0.044 0.009 0.019phthalazinyl)amino)phenyl)thio)thieno[3, 2-b]pyridine-2-carbonitrile 4624-phenyl-N-(4-(1H-pyrrolo[3,2- 446 B1 0.557 0.010 0.043b]pyridin-7-ylthio)phenyl)-1- phthalazinamine 4634-(4-chlorophenyl)-N-(4-(1H- 480 B2 0.146 0.008 0.010pyrrolo[3,2-b]pyridin-7- ylthio)phenyl)-1-phthalazinamine 4644-(4-methyl-2-thienyl)-N-(4-(1H- 466 B3 0.088 0.006 0.001pyrrolo[3,2-b]pyridin-7- ylthio)phenyl)-1-phthalazinamine 4654-(4-chlorophenyl)-N-(4-(furo[3,2- 481 unique 0.093 0.012 0.020b]pyridin-7-ylthio)phenyl)-1- phthalazinamine 466N-(4-(furo[3,2-b]pyridin-7- 447 B3 0.431 0.013 0.086ylthio)phenyl)-4-phenyl-1- phthalazinamine 4674-(1,3-benzodioxol-5-yl)-N-(4- 491 unique 0.095 0.010 0.016(furo[3,2-b]pyridin-7- ylthio)phenyl)-1-phthalazinamine 468N-(4-(furo[3,2-b]pyridin-7- 467 unique 0.129 0.029 0.014ylthio)phenyl)-4-(4-methyl-2- thienyl)-1-phthalazinamine 4694-(4-chlorophenyl)-N-(4-((1-(2- 538 B3 0.110 0.053 0.003(methyloxy)ethyl)-1H-pyrrolo[3,2- b]pyridin-7-yl)thio)phenyl)-1-phthalazinamine 470 N-(4-((1-(2-(methyloxy)ethyl)-1H- 524 B2 0.041 0.051<0.002300 pyrrolo[3,2-b]pyridin-7- yl)thio)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine 471 4-(4-chlorophenyl)-N-(4-((1-(1- 522 B20.090 0.049 0.006 methylethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)thio)phenyl)-1- phthalazinamine 472N-(4-((1-(1-methylethyl)-1H- 508 B2 0.064 0.099 0.007pyrrolo[3,2-b]pyridin-7- yl)thio)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine 473 4-(3,4-bis((2- 636 A1 0.073 0.011 0.100(methyloxy)ethyl)oxy)phenyl)-N- (4-((7-(methyloxy)-1,5-naphthyridin-4-yl)thio)phenyl)-1- phthalazinamine 474 4-(4-((2- 562 A10.051 0.016 0.024 (methyloxy)ethyl)oxy)phenyl)-N-(4-((7-(methyloxy)-1,5- naphthyridin-4-yl)thio)phenyl)-1-phthalazinamine 475 4-(4-chlorophenyl)-N-(4-((6-((2- 610 B3 0.035 0.0260.017 ((2- (methyloxy)ethyl)oxy)ethyl)oxy)-1,5-naphthyridin-4-yl)thio)phenyl)- 1-phthalazinamine 4768-((4-((4-(4-chlorophenyl)-1- 610 B3 0.746 0.293 0.140phthalazinyl)amino)phenyl)thio)-1- (2-((2-(methyloxy)ethyl)oxy)ethyl)-1,5-naphthyridin-2(1H)-one 477 4-(3-amino-4-methylphenyl)-N-(4- 517 A10.009 0.026 0.001 ((7-(methyloxy)-1,5-naphthyridin- 4-yl)thio)phenyl)-1-phthalazinamine 478 N-(4-(furo[3,2-b]pyridin-7- 468 B3 2.026 0.074 0.381yloxy)phenyl)-4-(4-(methyloxy)-1- piperidinyl)-1-phthalazinamine 4794-(3-amino-4-methylphenyl)-N-(4- 476 B3 >125.000000 >125.000000 0.009(furo[3,2-b]pyridin-7- ylsulfanyl)phenyl)-1- phthalazinamine 4804-(3-amino-4-methylphenyl)-N-(4- 460 B3 0.162 0.013 0.112(furo[3,2-b]pyridin-7-yloxy)phenyl)- 1-phthalazinamine 481N-(4-(furo[3,2-b]pyridin-7- 462 B3 0.341 0.002 0.032ylsulfanyl)phenyl)-4-(6-methyl-3- pyridinyl)-1-phthalazinamine 482N-(4-(furo[3,2-b]pyridin-7- 462 B3 0.415 0.004 0.036ylsulfanyl)phenyl)-4-(5-methyl-2- pyridinyl)-1-phthalazinamine 4834-(4-chlorophenyl)-N-(4-(furo[3,2- 465 B3 0.583 0.013 0.102b]pyridin-7-yloxy)phenyl)-1- phthalazinamine 3914-(5-chloro-2-pyridinyl)-N-(4- 482 unique 0.601 0.018 0.032(furo[3,2-b]pyridin-7- ylsulfanyl)phenyl)-1- phthalazinamine 4844-chloro-N-(4-((2- 477 B3 >125.000000 0.107 >1.200000(trimethylsilyl)furo[3,2-b]pyridin-7- yl)sulfanyl)phenyl)-1-phthalazinamine 485 N-(4-(furo[3,2-b]pyridin-7- 478 unique 0.479 0.0050.069 ylsulfanyl)phenyl)-4-(6-methoxy-3- pyridinyl)-1-phthalazinamine398 4-(3-fluoro-4-methylphenyl)-N-(4- 479 unique 1.729 0.059 0.009(furo[3,2-b]pyridin-7- ylsulfanyl)phenyl)-1- phthalazinamine 4864-(4-chlorophenyl)-N-(4-((2- 521 B3 0.141 0.018 0.002cyclopropylfuro[3,2-b]pyridin-7- yl)sulfanyl)phenyl)-1- phthalazinamine487 4-(3-amino-4-methylphenyl)-N-(4- 516 B3 0.006((2-cyclopropylfuro[3,2-b]pyridin-7- yl)sulfanyl)phenyl)-1-phthalazinamine 488 N-(4-(furo[3,2-b]pyridin-7- 462 B3 1.295 0.015 0.241ylsulfanyl)phenyl)-4-(6-methyl-2- pyridinyl)-1-phthalazinamine 4897-((4-((4-(4-chlorophenyl)-1- 506 B3 0.090 0.019 0.017phthalazinyl)amino)phenyl)sulfanyl)furo[3, 2-b]pyridine-2-carbonitrile490 7-((4-((4-(3-amino-4- 501 B3 0.090 0.013 0.009 methylphenyl)-1-phthalazinyl)amino)phenyl)sulfanyl)furo[3, 2-b]pyridine-2-carbonitrile491 4-(4-chlorophenyl)-N-(4-((2- 495 B3 0.150 0.039 0.037methylfuro[3,2-b]pyridin-7- yl)sulfanyl)phenyl)-1- phthalazinamine 4924-(3-amino-4-methylphenyl)-N-(4- 490 B3 0.142 0.046 0.021((2-methylfuro[3,2-b]pyridin-7- yl)sulfanyl)phenyl)-1- phthalazinamine493 4-(5-chloro-2-pyridinyl)-N-(4-(1,5- 493 B3 0.020 0.002 0.016naphthyridin-4-ylthio)phenyl)-1- phthalazinamine 494N-(4-((7-(methyloxy)-1,6- 508 B3 0.026 0.017 0.009naphthyridin-4-yl)thio)phenyl)-4- (4-methyl-2-thienyl)-1-phthalazinamine 495 4-(2-fluorophenyl)-N-(4-((7- 506 A1 0.150 0.0260.024 (methyloxy)-1,5-naphthyridin-4- yl)thio)phenyl)-1-phthalazinamine399 N-(4-((6-amino-4- 472 unique 0.286 0.025 0.019quinolinyl)thio)phenyl)-4-phenyl-1- phthalazinamine 4964-phenyl-N-(4-((7- 525 C2 1.037 0.374 0.397 ((trifluoromethyl)oxy)-4-quinolinyl)oxy)phenyl)-1- phthalazinamine 497 4-phenyl-N-(4-((7- 541B3 >25.000000 0.333 0.079 ((trifluoromethyl)oxy)-4-quinolinyl)thio)phenyl)-1- phthalazinamine 4984-(4-chlorophenyl)-N-(4-((7- 559 B3 0.183 0.165 0.078((trifluoromethyl)oxy)-4- quinolinyl)oxy)phenyl)-1- phthalazinamine 4994-(4-methyl-2-thienyl)-N-(4-((7- 561 B3 0.277 0.363 0.052((trifluoromethyl)oxy)-4- quinolinyl)thio)phenyl)-1- phthalazinamine 5008-((4-((4-(4-chlorophenyl)-1- 506 unique >25.000000 4.170 >1.200000phthalazinyl)(methyl)amino)phenyl)oxy)- 1,5-naphthyridin-2(1H)-one 5014-(1-benzofuran-5-yl)-N-(4-((7- 528 A1 0.029 0.058 0.014(methyloxy)-1,5-naphthyridin-4- yl)thio)phenyl)-1-phthalazinamine 5024-(2-methyl-2H-indazol-6-yl)-N-(4- 542 A1 0.027 0.009 0.006((7-(methyloxy)-1,5-naphthyridin- 4-yl)thio)phenyl)-1- phthalazinamine503 N-(4-((7-(methyloxy)-1,5- 510 A5 0.020 0.007 0.014naphthyridin-4-yl)thio)phenyl)-4- (4-methyl-1-piperazinyl)-1-phthalazinamine 504 4-(2,1,3-benzoxadiazol-5-yl)-N-(4- 530 A1 0.0170.032 0.006 ((7-(methyloxy)-1,5-naphthyridin- 4-yl)thio)phenyl)-1-phthalazinamine 505 4-(2-(ethyloxy)-1,3-thiazol-4-yl)-N- 539 A2 0.0160.014 0.022 (4-((7-(methyloxy)-1,5- naphthyridin-4-yl)thio)phenyl)-1-phthalazinamine 506 N-(4-((7-(methyloxy)-1,5- 495 A2 0.748 0.089 0.067naphthyridin-4-yl)thio)phenyl)-4- (1,3-thiazol-4-yl)-1- phthalazinamine507 4-(4-(2,2-difluoroethyl)-1- 560 A5 0.152 0.042 0.018piperazinyl)-N-(4-((7-(methyloxy)- 1,5-naphthyridin-4-yl)thio)phenyl)-1-phthalazinamine 508 N-(4-((7-methoxy-1,5- 515 A5 0.082 0.009 0.072naphthyridin-4-yl)sulfanyl)phenyl)- N′-(3-(methylsulfanyl)propyl)-1,4-phthalazinediamine 509 4-(6-methoxy-3-pyridinyl)-N-(4- 489 A1 0.3170.013 0.008 (1,5-naphthyridin-4- ylsulfanyl)phenyl)-1- phthalazinamine510 6,7-difluoro-4-(4-methyl-2- 498 A1 0.320 0.050 0.017thiophenyl)-N-(4-(1,5- naphthyridin-4-yloxy)phenyl)-1- phthalazinamine401 N-(4-((7-methoxy-1,5- 493 unique 0.847 0.052 0.187naphthyridin-4-yl)sulfanyl)phenyl)- 4-(1,2,3,6-tetrahydro-4-pyridinyl)-1-phthalazinamine 511 N-(4-((7-methoxy-1,5- 470 A4 0.585 0.069 0.094naphthyridin-4-yl)sulfanyl)phenyl)- 4-(1-methylethoxy)-1-phthalazinamine 512 4-ethoxy-N-(4-((7-methoxy-1,5- 456 A4 0.501 0.1200.033 naphthyridin-4-yl)sulfanyl)phenyl)- 1-phthalazinamine 513N-(4-((7-methoxy-1,5- 510 A4 0.231 0.030 0.059naphthyridin-4-yl)sulfanyl)phenyl)- 4-(2,2,2-trifluoroethoxy)-1-phthalazinamine 514 N-(4-((7-methoxy-1,5- 458 A4 0.189 0.010 0.020naphthyridin-4-yl)sulfanyl)phenyl)- 4-(methylsulfanyl)-1-phthalazinamine 515 4-(2-methoxyethoxy)-N-(4-((7- 486 A4 0.072 0.0120.018 methoxy-1,5-naphthyridin-4- yl)sulfanyl)phenyl)-1- phthalazinamine516 4-(3-chlorophenyl)-N-(4-((7- 522 B3 0.088 0.068 0.025(methyloxy)-1,5-naphthyridin-4- yl)thio)phenyl)-1-phthalazinamine 5174-(1,3-benzodioxol-5-yl)-N-(4-(4- 501 B3 0.150 0.017 0.011quinolinylthio)phenyl)-1- phthalazinamine 518 4-(3-chlorophenyl)-N-(4-497 A1 0.218 0.010 0.016 (thieno[3,2-b]pyridin-7-ylthio)phenyl)-1-phthalazinamine 519 N-(3-fluoro-4-((7-(methyloxy)-1,5-506 B3 0.083 0.053 0.009 naphthyridin-4-yl)thio)phenyl)-4-phenyl-1-phthalazinamine 520 N-(4-((7-(methyloxy)-1,5- 524 A5 0.0270.017 0.004 naphthyridin-4-yl)thio)phenyl)-4-(4-(methyloxy)-1-piperidinyl)-1- phthalazinamine 521N-(4-((7-(methyloxy)-1,5- 481 A5 0.112 0.025 0.021naphthyridin-4-yl)thio)phenyl)-4- (1-pyrrolidinyl)-1-phthalazinamine 5224-(1,3-benzodioxol-5-yl)-N-(3- 550 B3 0.009 0.022 0.001fluoro-4-((7-(methyloxy)-1,5- naphthyridin-4-yl)thio)phenyl)-1-phthalazinamine 523 N-(4-((7-(methyloxy)-1,5- 563 A5 0.036 0.144 0.006naphthyridin-4-yl)thio)phenyl)-4- (4-(trifluoromethyl)-1-piperidinyl)-1-phthalazinamine 524 N-methyl-N′-(4-((7-(methyloxy)- 482 A5 0.093 0.0991,5-naphthyridin-4-yl)thio)phenyl)- N-propyl-1,4-phthalazinediamine 5254-(4-methyl-3-(methyloxy)phenyl)- 516 A1 0.013 0.028N-(4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 526 N-(4-((7-(methyloxy)-1,5- 496 A5 0.294 0.032 0.025naphthyridin-4-yl)thio)phenyl)-4- (4-morpholinyl)-1-phthalazinamine 5274-(4-chloro-1-piperidinyl)-N-(4-((7- 530 A5 0.036 0.138 0.004(methyloxy)-1,5-naphthyridin-4- yl)thio)phenyl)-1-phthalazinamine 528N-(3-fluoro-4-((7-(methyloxy)-1,5- 526 B3 0.064 0.293 0.009naphthyridin-4-yl)thio)phenyl)-4- (4-methyl-2-thienyl)-1-phthalazinamine 529 4-(4-methyl-3-(methyloxy)phenyl)- 532 B3 0.020 0.0370.006 N-(4-((7-(methyloxy)-1,5- naphthyridin-4-yl)thio)phenyl)-1-phthalazinamine 530 4-(1,3-benzodioxol-5-yl)-N-(4-((7- 532 B3 0.0140.014 0.001 (methyloxy)-1,5-naphthyridin-4-yl)thio)phenyl)-1-phthalazinamine 5314-(4,4-difluoro-1-piperidinyl)-N-(4- 531 A5 0.089 0.024 0.049((7-(methyloxy)-1,5-naphthyridin- 4-yl)thio)phenyl)-1- phthalazinamine532 N-(4-((7-(methyloxy)-1,5- 525 A5 0.061 0.019 0.020naphthyridin-4-yl)thio)phenyl)-4- ((3R)-3-(methyloxy)-1-piperidinyl)-1-phthalazinamine 533 N-(2-(methyloxy)ethyl)-N′-(4-((7- 485 A5 0.0450.030 0.062 (methyloxy)-1,5-naphthyridin-4- yl)thio)phenyl)-1,4-phthalazinediamine 534 4-((4-((4-(4-(methyloxy)-1- 519 A5 0.035 0.0200.006 piperidinyl)-1- phthalazinyl)amino)phenyl)thio)-7-quinolinecarbonitrile 535 N-(4-((7-(methyloxy)-1,5- 499 A5 0.022 0.0200.026 naphthyridin-4-yl)thio)phenyl)-N′- (3-(methyloxy)propyl)-1,4-phthalazinediamine 536 4-chloro-N-(4-((7-methoxy-1,5- 446 B3 0.812 0.0310.031 naphthyridin-4-yl)sulfanyl)phenyl)- 1-phthalazinamine 537N-(4-((7-methoxy-1,5- 532 A5 0.198 0.111 0.002naphthyridin-4-yl)sulfanyl)phenyl)- N′-(2-(2-pyridinyl)ethyl)-1,4-phthalazinediamine 538 N-(4-((7-methoxy-1,5- 564 A5 3.432 0.045 0.178naphthyridin-4-yl)sulfanyl)phenyl)-4-(4-(1-pyrrolidinyl)-1-piperidinyl)- 1-phthalazinamine 5394-(3,5-difluorophenyl)-N-(4-((7- 508 A1 0.133 0.020 0.081methoxy-1,5-naphthyridin-4- yl)oxy)phenyl)-1-phthalazinamine 540N-(4-((7-methoxy-1,5- 511 A5 0.013 naphthyridin-4-yl)sulfanyl)phenyl)-4-((3R)-3-methoxy-1-pyrrolidinyl)- 1-phthalazinamine 4024-methoxy-N-(4-((7-methoxy-1,5- 442 unique 0.167 0.015 0.066naphthyridin-4-yl)sulfanyl)phenyl)- 1-phthalazinamine 403N-(4-((7-methoxy-1,5- 539 unique 0.239 0.005 0.037naphthyridin-4-yl)sulfanyl)phenyl)- 4-(2-(2-piperidinyl)ethoxy)-1-phthalazinamine 541 4-cyclopropyl-N-(4-((7-methoxy- 452 B3 0.393 0.0250.038 1,5-naphthyridin-4- yl)sulfanyl)phenyl)-1- phthalazinamine 542N-(4-((7-methoxy-1,5- 396 B3 0.319 0.041 0.382naphthyridin-4-yl)oxy)phenyl)-1- phthalazinamine 5434-cyclopropyl-N-(4-((7-methoxy- 436 B3 0.581 0.044 0.2811,5-naphthyridin-4-yl)oxy)phenyl)- 1-phthalazinamine 4044-((4-((7-methoxy-1,5- 437 unique 0.447 0.009 0.063 naphthyridin-4-yl)sulfanyl)phenyl)amino)-1- phthalazinecarbonitrile 5444-(3-amino-4-methylphenyl)-N-(4- 470 B3 0.126 0.012 0.008(4-quinolinyloxy)phenyl)-1- phthalazinamine 5444-(4-chlorophenyl)-6,7-difluoro-N- 542 A1 0.116 0.031 0.041(4-((7-methoxy-1,5-naphthyridin-4- yl)oxy)phenyl)-1-phthalazinamine 5454-(3-amino-4-methylphenyl)-6,7- 537 A1 0.085 0.020 0.012difluoro-N-(4-((7-methoxy-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 546 4-(2-chlorophenyl)-N-(4-((7- 507 A1 0.723 0.135methoxy-1,5-naphthyridin-4- yl)oxy)phenyl)-1-phthalazinamine 547N-(4-((7-methoxy-1,5- 412 B3 0.335 0.020naphthyridin-4-yl)sulfanyl)phenyl)- 1-phthalazinamine 548N-(4-((6-(methyloxy)-1,5- 495 B3 0.270 0.031 0.036naphthyridin-4-yl)thio)phenyl)-4- (1-piperidinyl)-1-phthalazinamine 549N-(4-((6-(methyloxy)-1,5- 508 B3 0.098 0.064 0.009naphthyridin-4-yl)thio)phenyl)-4- (4-methyl-2-thienyl)-1-phthalazinamine 550 4-(5-chloro-2-pyridinyl)-N-(4-((6- 523 B3 0.1070.022 0.016 (methyloxy)-1,5-naphthyridin-4-yl)thio)phenyl)-1-phthalazinamine 551 4-(1,3-benzodioxol-5-yl)-N-(4-((6-516 B3 0.096 0.017 0.002 (methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 552 N-(4-((6-(methyloxy)-1,5- 492 B30.056 0.036 0.010 naphthyridin-4-yl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1- phthalazinamine 5534-(6-methyl-3-pyridinyl)-N-(4-(1,5- 473 A1 0.042 0.005 0.001naphthyridin-4-ylthio)phenyl)-1- phthalazinamine 554N-(4-((6-(methyloxy)-4- 486 B3 0.172 0.011 0.108quinolinyl)oxy)phenyl)-4-(5- methyl-2-pyridinyl)-1- phthalazinamine 5554-(3,3-dimethyl-1-piperidinyl)-N- 523 A5 0.102 0.105 0.064(4-((7-(methyloxy)-1,5- naphthyridin-4-yl)thio)phenyl)-1-phthalazinamine 556 4-(3,5-dimethyl-1-piperidinyl)-N- 523 A5 0.116 0.1590.026 (4-((7-(methyloxy)-1,5- naphthyridin-4-yl)thio)phenyl)-1-phthalazinamine 557 4-(4-fluoro-1-piperidinyl)-N-(4-((7- 513 A5 0.1610.059 0.026 (methyloxy)-1,5-naphthyridin-4-yl)thio)phenyl)-1-phthalazinamine 558 4-(1-methylethyl)-N-(4-((7- 454 B30.378 0.041 0.100 (methyloxy)-1,5-naphthyridin-4-yl)thio)phenyl)-1-phthalazinamine 559 4-(4-chlorophenyl)-N-(4-((2- 511B3 0.168 0.098 0.018 methylthieno[3,2-b]pyridin-7-yl)thio)phenyl)-1-phthalazinamine 560 4-(5-chloro-2-pyridinyl)-N-(4-((2-512 B3 0.416 0.081 0.023 methylthieno[3,2-b]pyridin-7-yl)thio)phenyl)-1-phthalazinamine 561 4-phenyl-N-(4-(4- 458B3 >25.000000 >5.000000 >1.200000 quinazolinylthio)phenyl)-1-phthalazinamine 562 4-(4-chlorophenyl)-N-(4-(4- 476 C2 0.107 0.006 0.026quinazolinyloxy)phenyl)-1- phthalazinamine 5634-((8aS)-hexahydropyrrolo[1,2- 536 A5 0.023 0.009 <0.002300a]pyrazin-2(1H)-yl)-N-(4-((7- (methyloxy)-1,5-naphthyridin-4-yl)thio)phenyl)-1-phthalazinamine 4058-((4-((4-(5-chloro-2-pyridinyl)-1- 509 unique 0.042 0.007 0.036phthalazinyl)amino)phenyl)thio)- 1,5-naphthyridin-2(1H)-one 5644-(4-chlorophenyl)-N-(4-((6- 506 C2 >25.000000 0.129 0.043(methyloxy)-4- quinazolinyl)oxy)phenyl)-1- phthalazinamine 565N-(4-((6-(methyloxy)-4- 492 C2 0.686 0.108 0.030quinazolinyl)oxy)phenyl)-4-(4- methyl-2-thienyl)-1- phthalazinamine 5664-(4-chlorophenyl)-N-(3- 536 B3 0.093 0.043 0.191(methyloxy)-4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 567 N-(3-(methyloxy)-4-((7- 522 B3 0.092 0.041 0.227(methyloxy)-1,5-naphthyridin-4- yl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine 568 4-(4-methyl-2-thienyl)-N-(4-(4- 462 C20.233 0.011 0.034 quinazolinyloxy)phenyl)-1- phthalazinamine 5698-((4-((4-(4-chlorophenyl)-1- 492 unique 0.128 0.013 0.115phthalazinyl)amino)phenyl)oxy)- 1,5-naphthyridin-2(1H)-one 5704-(4-chlorophenyl)-N-(4-(5,6,7,8- 496 B3 0.050 0.008 0.008tetrahydro-1,8-naphthyridin-4- ylthio)phenyl)-1-phthalazinamine 5714-phenyl-N-(4-((6- 541 B3 >25.000000 >25.000000 0.060((trifluoromethyl)oxy)-4- quinolinyl)thio)phenyl)-1- phthalazinamine 5724-(4-methyl-2-thienyl)-N-(4-((6- 561 B3 >25.000000 >25.000000 0.055((trifluoromethyl)oxy)-4- quinolinyl)thio)phenyl)-1- phthalazinamine 573N-(4-((5,7-bis(methyloxy)-4- 522 C2 0.042 0.114 0.011quinazolinyl)oxy)phenyl)-4-(4- methyl-2-thienyl)-1- phthalazinamine 5744-(4-chlorophenyl)-N-(4-((6- 559 B3 0.752 0.365 0.119((trifluoromethyl)oxy)-4- quinolinyl)oxy)phenyl)-1- phthalazinamine 5754-(4-methyl-2-thienyl)-N-(4-((6- 545 B3 0.226 0.810 0.112((trifluoromethyl)oxy)-4- quinolinyl)oxy)phenyl)-1- phthalazinamine 5764-(5,6-dihydroimidazo[1,2- 533 A5 0.077 0.026 0.013a]pyrazin-7(8H)-yl)-N-(4-((7- (methyloxy)-1,5-naphthyridin-4-yl)thio)phenyl)-1-phthalazinamine 577 4-phenyl-N-(4-(5,6,7,8-tetrahydro-462 B3 0.428 0.021 0.025 1,8-naphthyridin-4-ylthio)phenyl)-1-phthalazinamine 578 4-(6,7-dihydrothieno[3,2-c]pyridin- 549 A5 0.0330.081 0.007 5(4H)-yl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)thio)phenyl)-1- phthalazinamine 5794-(5,6-dihydro[1,2,4]triazolo[1,5- 534 A5 0.228 0.032 0.054a]pyrazin-7(8H)-yl)-N-(4-((7- (methyloxy)-1,5-naphthyridin-4-yl)thio)phenyl)-1-phthalazinamine 580 N-(4-((7-(methyloxy)-1,5- 550 A50.023 0.005 0.005 naphthyridin-4-yl)thio)phenyl)-4-((9aR)-octahydro-2H-pyrido[1,2- a]pyrazin-2-yl)-1-phthalazinamine 581N-(4-((5,7-bis(methyloxy)-4- 518 B1 1.131 0.236 0.036quinazolinyl)thio)phenyl)-4-phenyl- 1-phthalazinamine 5824-((8aR)-hexahydropyrrolo[1,2- 536 A5 0.029 0.006 0.006a]pyrazin-2(1H)-yl)-N-(4-((7- (methyloxy)-1,5-naphthyridin-4-yl)thio)phenyl)-1-phthalazinamine 583 N-(4-((7-(methyloxy)-1,5- 519 A10.028 0.008 0.005 naphthyridin-4-yl)thio)phenyl)-4-(6-(methyloxy)-3-pyridinyl)-1- phthalazinamine 584N-(4-((7-(methyloxy)-1,5- 550 A5 0.009 0.005 0.005naphthyridin-4-yl)thio)phenyl)-4- ((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)-1-phthalazinamine 585 N-(4-((7-(methyloxy)-1,5- 550 A50.036 0.006 0.018 naphthyridin-4-yl)thio)phenyl)-4-((9aS)-octahydro-2H-pyrido[1,2- a]pyrazin-2-yl)-1-phthalazinamine 586N-(4-((7-(methyloxy)-1,5- 533 C2 0.124 0.042 0.028naphthyridin-4-yl)oxy)phenyl)-4- ((4aR,8aS)-octahydro-2(1H)-isoquinolinyl)-1-phthalazinamine 587 N-(4-((7-(methyloxy)-1,5- 533 C20.217 0.033 0.140 naphthyridin-4-yl)oxy)phenyl)-4-((4aS,8aR)-octahydro-2(1H)- isoquinolinyl)-1-phthalazinamine 588N-(4-((7-(methyloxy)-1,5- 503 A1 0.051 0.017 0.004naphthyridin-4-yl)thio)phenyl)-4- (6-methyl-3-pyridinyl)-1-phthalazinamine 589 8-((4-((4-(4-methyl-2-thienyl)-1- 494 unique 0.0190.008 0.007 phthalazinyl)amino)phenyl)thio)- 1,5-naphthyridin-2(1H)-one590 N-(4-((5,7-bis(methyloxy)-4- 536, B3 0.027 0.020 0.004quinazolinyl)oxy)phenyl)-4-(4- 538 chlorophenyl)-1-phthalazinamine 5914-(4-chlorophenyl)-N-(4- 482, C1 0.250 0.005 0.115(thieno[3,2-d]pyrimidin-4- 484 yloxy)phenyl)-1-phthalazinamine 5924-((4-((4-phenyl-1- 466 C1 0.338 0.022 0.147phthalazinyl)amino)phenyl)oxy)-6- quinolinecarbonitrile 5934-((methyloxy)methyl)-N-(4-((7- 466 B4 0.526 0.082 >1.200000(methyloxy)-1,5-naphthyridin-4- yl)oxy)phenyl)-6-phenyl-3-pyridazinamine 594 6-(1,3-benzodioxol-5-yl)-4-ethyl-N- 494 B4 0.0940.051 0.202 (4-((7-(methyloxy)-1,5- naphthyridin-4-yl)oxy)phenyl)-3-pyridazinamine 595 N-(4-ethyl-6-(4-methylphenyl)-3- 463 C4 0.102 0.0230.083 pyridazinyl)-N′-(7-(methyloxy)-1,5- naphthyridin-4-yl)-1,4-benzenediamine 596 4-((4-((4-ethyl-6-(4-methylphenyl)- 457 C4 0.1600.058 0.084 3- pyridazinyl)amino)phenyl)amino)- 7-quinolinecarbonitrile597 N-(4-((6,7-bis(methyloxy)-1,5- 518 B1 0.246 0.681 0.061naphthyridin-4-yl)thio)phenyl)-4- phenyl-1-phthalazinamine 598N-(4-((6,7-bis(methyloxy)-1,5- 552, B3 0.135 0.595 0.028naphthyridin-4-yl)thio)phenyl)-4- 554 (4-chlorophenyl)-1-phthalazinamine 599 N-(4-((7-bromopyrido[3,2- 521, C2 0.7940.256 >1.200000 d]pyrimidin-4-yl)oxy)phenyl)-4- 523phenyl-1-phthalazinamine 406 8-((4-((4-(4-chlorophenyl)-1- 538, unique0.034 0.186 <0.002300 phthalazinyl)amino)phenyl)thio)-3- 540(methyloxy)-1,5-naphthyridin- 2(1H)-one 600 4-((7R,8aS)-7- 554 A5 0.0140.010 0.007 fluorohexahydropyrrolo[1,2- a]pyrazin-2(1H)-yl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4- yl)thio)phenyl)-1-phthalazinamine 407(5-(4-((4-((7-(methyloxy)-1,5- 508 unique 0.016 0.004 0.012naphthyridin-4- yl)oxy)phenyl)amino)-1- phthalazinyl)-3-thienyl)methanol601 4-((8aS)-7,7- 572 A5 0.021 0.012 0.005 difluorohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(4-((7- (methyloxy)-1,5-naphthyridin-4-yl)thio)phenyl)-1-phthalazinamine 4084-(4-(fluoromethyl)-2-thienyl)-N-(4- 510 unique 0.024 0.009 0.025((7-(methyloxy)-1,5-naphthyridin- 4-yl)oxy)phenyl)-1- phthalazinamine602 4-((8aR)-7,7- 556 B2 0.018 0.013 0.051 difluorohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(4-((7- (methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine 602 N-(4-((7-(methyloxy)-1,5- 564 A50.017 0.005 0.012 naphthyridin-4-yl)thio)phenyl)-4-((10aR)-octahydropyrazino[1,2- a]azepin-2(1H)-yl)-1- phthalazinamine 604N-(4-((7-(methyloxy)-1,5- 548 B2 0.027 0.013 0.087naphthyridin-4-yl)oxy)phenyl)-4- ((10aR)-octahydropyrazino[1,2-a]azepin-2(1H)-yl)-1- phthalazinamine 605 N-(4-((7-(methyloxy)-1,5- 574A5 0.803 0.083 0.018 naphthyridin-4-yl)thio)phenyl)-4-(4-(methylsulfonyl)-1-piperazinyl)- 1-phthalazinamine 606N-(6-((5,7-bis(methyloxy)-4- 503 B4 >25.000000 0.035 0.292quinazolinyl)oxy)-3-pyridinyl)-4- phenyl-1-phthalazinamine 607N-(4-((7-methoxy-1,5- 558 B2 2.822 0.324 0.482naphthyridin-4-yl)oxy)phenyl)-4- (4-(methylsulfonyl)-1-piperazinyl)-1-phthalazinamine 608 4-(4-acetyl-1-piperazinyl)-N-(4-((7- 538 A5 0.3520.022 0.016 methoxy-1,5-naphthyridin-4- yl)sulfanyl)phenyl)-1-phthalazinamine 609 4-ethyl-N-(4-((7-methoxy-1,5- 496 B4 0.123 0.0200.055 naphthyridin-4-yl)sulfanyl)phenyl)- 6-(2-methoxyphenyl)-3-pyridazinamine 409 8-(4-((4-(4-chlorophenyl)-1- 492, unique 0.020 0.0050.032 phthalazinyl)amino)phenoxy)-1,5- 494 naphthyridin-3-ol 610N-(4-((7-(benzyloxy)-1,5- 582, C2 0.047 0.033 0.014naphthyridin-4-yl)oxy)phenyl)-4- 584 (4-chlorophenyl)-1- phthalazinamine611 470 A1 >125.000 0.671 >1.2000 612 471 C1 0.684 0.023 4104-(4-fluorophenyl)-N-(4-((7- 522.1 unique 0.532 0.645 0.260(methyloxy)-1,5-naphthyridin-4- yl)sulfinyl)phenyl)-1- phthalazinamine613 4-(4-chlorophenyl)-N-(4-(1-(7- 517.2 B3 >25.000000 0.243 >1.200000(methyloxy)-4- quinolinyl)ethyl)phenyl)-1- phthalazinamine 614(4-((4-(4-chlorophenyl)-1- 519.1 B3 0.223 0.046 0.053phthalazinyl)amino)phenyl)(7- (methyloxy)-4-quinolinyl)methanol 615(4-((4-(4-chlorophenyl)-1- 517.2 B3 0.300 0.039 0.150phthalazinyl)amino)phenyl)(7- (methyloxy)-4- quinolinyl)methanone

The invention further provides methods for making compounds of FormulasI-IV. For example, and in one embodiment, there is provided a method ofmaking a compound of Formula I, the method comprising the step ofreacting compound of Formula A

with a compound of Formula B

wherein A⁸ and R of the compound of formula A and A′, A², D′, L¹, R¹,A³⁻⁶ and n of the compound of formula B are as defined herein, to make acompound of Formula I. This method may also be used to make a compoundof Formulas II, III and IV.

While the examples described above provide processes for synthesizingcompounds of Formulas I-IV, other methods may be utilized to preparesuch compounds. In the procedures described herein, the steps may beperformed in an alternate order and may be preceded, or followed, byadditional protection/deprotection steps as necessary.

Methods involving the use of protecting groups may be used.Particularly, if one or more functional groups, for example carboxy,hydroxy, amino, or mercapto groups, are or need to be protected inpreparing the compounds of the invention, because they are not intendedto take part in a specific reaction or chemical transformation, variousknown conventional protecting groups may be used. For example,protecting groups typically utilized in the synthesis of natural andsynthetic compounds, including peptides, nucleic acids, derivativesthereof and sugars, having multiple reactive centers, chiral centers andother sites potentially susceptible to the reaction reagents and/orconditions, may be used.

The protecting groups may already be present in precursors and shouldprotect the functional groups concerned against unwanted secondaryreactions, such as acylations, etherifications, esterifications,oxidations, solvolysis, and similar reactions. It is a characteristic ofprotecting groups that they readily lend themselves, i.e. withoutundesired secondary reactions, to removal, typically accomplished bysolvolysis, reduction, photolysis or other methods of removal such as byenzyme activity, under conditions analogous to physiological conditions.It should also be appreciated that the protecting groups should not bepresent in the end-products. Those of ordinary skill in the art know, orcan easily establish, which protecting groups are suitable with thereactions described herein.

The protection of functional groups by protecting groups, the protectinggroups themselves, and their removal reactions (commonly referred to as“deprotection”) are described, for example, in standard reference works,such as J. F. W. McOmie, Protective Groups in Organic Chemistry, PlenumPress, London and New York (1973), in T. W. Greene, Protective Groups inOrganic Synthesis, Wiley, New York (1981), in The Peptides, Volume 3, E.Gross and J. Meienhofer editors, Academic Press, London and New York(1981), in Methoden der Organischen Chemie (Methods of OrganicChemistry), Houben Weyl, 4^(th) edition, Volume 15/1, Georg ThiemeVerlag, Stuttgart (1974), in H.-D. Jakubke and H. Jescheit, Aminosäuren,Peptide, Proteine (Amino Acids, Peptides, Proteins), Verlag Chemie,Weinheim, Deerfield Beach, and Basel (1982), and in Jochen Lehmann,Chemie der Kohlenhydrate: Monosaccharide und Derivate (Chemistry ofCarbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag,Stuttgart (1974).

The procedures may further use appropriate reaction conditions,including inert solvents, additional reagents, such as bases (e.g., LDA,DIEA, pyridine, K₂CO₃, and the like), catalysts, and salt forms of theabove. The intermediates may be isolated or carried on in situ, with orwithout purification. Purification methods are known in the art andinclude, for example, crystallization, chromatography (liquid and gasphase, and the like), extraction, distillation, trituration, reversephase HPLC and the like, many of which were utilized in the Examplesabove. Reactions conditions such as temperature, duration, pressure, andatmosphere (inert gas, ambient) are known in the art and may be adjustedas appropriate for the reaction.

All synthetic procedures described herein can be carried out either inthe absence or in the presence (usually) of solvents or diluents. Asappreciated by those of ordinary skill in the art, the solvents shouldbe inert with respect to, and should be able to dissolve, the startingmaterials and other reagents used. Solvents should be able to partiallyor wholly solubilize the reactants in the absence or presence ofcatalysts, condensing agents or neutralizing agents, for example ionexchangers, typically cation exchangers for example in the H⁺ form. Theability of the solvent to allow and/or influence the progress or rate ofthe reaction is generally dependant on the type and properties of thesolvent(s), the reaction conditions including temperature, pressure,atmospheric conditions such as in an inert atmosphere under argon ornitrogen, and concentration, and of the reactants themselves.

Suitable solvents for conducting reactions to synthesize compounds ofthe invention include, without limitation, water; esters, includinglower alkyl-lower alkanoates, e.g., EtOAc; ethers including aliphaticethers, e.g., Et₂O and ethylene glycol dimethylether or cyclic ethers,e.g., THF; liquid aromatic hydrocarbons, including benzene, toluene andxylene; alcohols, including MeOH, EtOH, 1-propanol, IPOH, n- andt-butanol; nitriles including CH₃CN; halogenated hydrocarbons, includingCH₂Cl₂, CHCl₃ and CCl₄; acid amides including DMF; sulfoxides, includingDMSO; bases, including heterocyclic nitrogen bases, e.g. pyridine;carboxylic acids, including lower alkanecarboxylic acids, e.g., AcOH;inorganic acids including HCl, HBr, HF, H₂SO₄ and the like; carboxylicacid anhydrides, including lower alkane acid anhydrides, e.g., aceticanhydride; cyclic, linear, or branched hydrocarbons, includingcyclohexane, hexane, pentane, isopentane and the like, and mixtures ofthese solvents, such as purely organic solvent combinations, orwater-containing solvent combinations e.g., aqueous solutions. Thesesolvents and solvent mixtures may also be used in “working-up” thereaction as well as in processing the reaction and/or isolating thereaction product(s), such as in chromatography.

The invention further includes salt forms of compounds of Formulas I,II, III and IV. Salts of a compound of the invention having asalt-forming group may be prepared in a conventional manner or mannerknown to persons skilled in the art. For example, acid addition salts ofcompounds of the invention may be obtained by treatment with an acid orwith a suitable anion exchange reagent. A salt with two acid molecules(for example a dihalogenide) may also be converted into a salt with oneacid molecule per compound (for example a monohalogenide); this may bedone by heating to a melt, or for example by heating as a solid under ahigh vacuum at elevated temperature, for example from 50° C. to 170° C.,one molecule of the acid being expelled per molecule of the compound.

Acid salts can usually be converted to free-base compounds, e.g. bytreating the salt with suitable basic agents, for example with alkalimetal carbonates, alkali metal hydrogen carbonates, or alkali metalhydroxides, typically potassium carbonate or sodium hydroxide. Suitableacid and base addition salts are further described in the DefinitionSection herein.

The invention further encompasses pro-drugs of compounds of Formulas I,II, III and IV. For example, a phosphate group may be a pro-drugderivative of an alcohol group or an amine group, or an ester may be apro-drug of a carboxylic acid functional group. Phosphate groups may beincorporated into desired compounds of Formulas I, II, III and IV inorder to improve upon in-vivo bioavailability and/or otherpharmacokinetic or pharmacodynamic properties of the compound.

The invention further encompasses “intermediate” compounds, includingstructures produced from the synthetic procedures described, whetherisolated or not, prior to obtaining the finally desired compound.Structures resulting from carrying out steps from a transient startingmaterial, structures resulting from divergence from the describedmethod(s) at any stage, and structures forming starting materials underthe reaction conditions are all “intermediates” included in theinvention. Further, structures produced by using starting materials inthe form of a reactive derivative or salt, or produced by a compoundobtainable by means of the process according to the invention andstructures resulting from processing the compounds of the invention insitu are also within the scope of the invention.

Starting materials of the invention, are either known, commerciallyavailable, or can be synthesized in analogy to or according to methodsthat are known in the art. Many starting materials may be preparedaccording to known processes and, in particular, can be prepared usingprocesses described in the examples. In synthesizing starting materials,functional groups may be protected with suitable protecting groups whennecessary. Protecting groups, their introduction and removal aredescribed above.

Compounds of the present invention can possess, in general, one or moreasymmetric carbon atoms and are thus capable of existing in the form ofoptical isomers as well as in the form of racemic or non-racemicmixtures thereof. The optical isomers can be obtained by resolution ofthe racemic mixtures according to conventional processes, e.g., byformation of diastereoisomeric salts, by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of theinvention with chiral reagents, such as an optically pure acid in anactivated form or an optically pure isocyanate. The synthesizeddiastereoisomers can be separated by conventional means such aschromatography, distillation, crystallization or sublimation, and thenhydrolyzed to deliver the enantiomerically pure compound. The opticallyactive compounds of the invention can likewise be obtained by usingoptically active starting materials. These isomers may be in the form ofa free acid, a free base, an ester or a salt.

The compounds of this invention may also be represented in multipletautomeric forms. The invention expressly includes all tautomeric formsof the compounds described herein.

The compounds may also occur in cis- or trans- or E- or Z-double bondisomeric forms. All such isomeric forms of such compounds are expresslyincluded in the present invention. All crystal forms of the compoundsdescribed herein are expressly included in the present invention.

Substituents on ring moieties (e.g., phenyl, thienyl, etc.) may beattached to specific atoms, whereby they are intended to be fixed tothat atom, or they may be drawn unattached to a specific atom, wherebythey are intended to be attached at any available atom that is notalready substituted by an atom other than H (hydrogen).

The synthetic chemistry transformations, as well as protecting groupmethodologies (protection and deprotection) described above and usefulin synthesizing the inhibitor compounds described herein, are known inthe art and include, for example, those such as described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^(rd)edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); A.Katritzky and A. Pozharski, Handbook of Heterocyclic Chemistry, 2^(nd)edition (2001); M. Bodanszky, A. Bodanszky, The Practice of PeptideSynthesis, Springer-Verlag, Berlin Heidelberg (1984); J. Seyden-Penne,Reductions by the Alumino- and Borohydrides in Organic Synthesis, 2^(nd)edition, Wiley-VCH, (1997); and L. Paquette, editor, Encyclopedia ofReagents for Organic Synthesis, John Wiley and Sons (1995).

The compounds of the invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and include those which increasebiological penetration into a given biological compartment (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion. By way of example, a compound ofthe invention may be modified to incorporate a hydrophobic group or“greasy” moiety in an attempt to enhance the passage of the compoundthrough a hydrophobic membrane, such as a cell wall.

BIOLOGICAL EVALUATION

Although the pharmacological properties of the compounds of theinvention (Formulas I-III) vary with structural change, in general,activity possessed by compounds of Formulas I-III may be demonstratedboth in vitro as well as in vivo. The following exemplifiedpharmacological assays have been carried out with the compoundsaccording to the invention. Briefly, representative compounds of theinvention were found to inhibit the activity of Aurora kinaseselectively or non-selectively, at doses less than 25 μM. This activitydemonstrates the utility of the compounds in the prophylaxis andtreatment of cellular proliferative disorders, including cancer asdescribed herein.

Aurora Kinase HTRF Assays AuroraA-TPX2-Homogeneous Time ResolvedFluorescent (HTRF) Kinase Assay:

The Aurora-A HTRF assay begins with Aurora-A in the presence of ATPphosphorylating the biotinylated peptide PLK. The reaction incubates forabout 120 min. Detection reagents are added to quench the reaction.These agents stop the reaction by diluting out the enzyme and chelatingthe metals due to the presence of EDTA. After addition, the assay isincubated overnight to allow the detection reagents to equilibrate.

The AuroraA HTRF assay comprises 1 μL of compound in 100% DMSO, 20 μL ofATP and biotinylated PLK, and 20 p-L of AuroraA-TPX2 KD GST for a finalvolume of about 41 μL. The final concentration of PLK is about 1 μM. Thefinal concentration of ATP is about 1 μM (Km(app)=1 μM+/−0.1) and thefinal concentration of AuroraA is about 5 nM. Buffer conditions are asfollows: 60 mM HEPES pH 7.5, 25 mM NaCl, 10 mM MgCl, 2 mM DTT, 0.05%BSA.

The assay is quenched and stopped with 160 μL of detection reagent.Detection reagents are as follows: Buffer made of 50 mM Tris, pH 7.5,100 mM NaCl, 3 mM EDTA, 0.05% BSA, 0.1% Tween20. Added to this bufferprior to reading is Steptavidin allophycocyanin (SA-APC) at a final concin the assay of 0.0005 mg/mL, and europilated anti-phosphoPLK Ab(Eu-anti-PLK) at a final conc of 0.02 nM.

The assay plate is read in either a Discovery or a RubyStar. Theeu-anti-PLK is excited at 320 nm and emits at 615 nm to excite theSA-APC which in turn emits at 655 nm. The ratio of SA-APC at 655 nm(excited due to close proximity to the Eu-anti-PLK because ofphosphorylation of the peptide) to free Eu-anti-PLK at 615 nm will givesubstrate phosphorylation.

Many of the Examples described herein were tested, and fund to be activecompounds. Table I includes related biological data, which may beinterpreted using the activity gauge below. Selected Examples 29-45 and74-370 exhibited an average activity in the Aurora kinase A HTRF assayas follows:

“+” represents an activity (IC₅₀) in the range of 2.5 uM-500 nM;“++” represents an activity (IC₅₀) in the range of 500-100 nM; and“+++” represents an activity (IC₅₀) of less than 100 nM.

AuroraB-Homogeneous Time Resolved Fluorescent (HTRF) Kinase Assay:

The AuroraB HTRF assay begins with AuroraB in the presence of ATPphosphorylating the biotinylated peptide Histone H3. The reactionincubates for about 90 min. the reaction is quentched by addition ofdetection reagents, which stop the reaction by diluting out the enzymeand chelating the metals due to the presence of EDTA. After addition,the assay is incubated for about 60 min to allow detection reagents toequilibrate.

The AuroraB HTRF assay comprises 1 μL of compound in 100% DMSO, 20 μL ofATP and biotinylated Histone H3, and 20 μL of AuroraB FL His for a finalvolume of 41 μL. The final concentration of Histone H3 is 0.1 μM. Thefinal concentration of ATP is 23 μM (Km(app)=23 μM+/−2.6) and the finalconcentration of AuroraB is 400 μM. Buffer conditions are as follows: 50mM HEPES pH 7.5, 5 mM NaCl, 0.5 mM MgCl, 0.5 mM MnCl, 2 mM DTT, 0.05%BSA.

The assay is quenched and stopped with 160 μL of detection reagent.Detection reagents are as follows: Buffer made of 50 mM Tris, pH 7.5,100 mM NaCl, 3 mM EDTA, 0.05% BSA, 0.1% Tween20. Added to this bufferprior to reading is Steptavidin allophycocyanin (SA-APC) at a final concin the assay of 0.001 mg/mL, and europilated anti-phosphoHistoneH3 Ab(Eu-anti-His H3) at a final conc of 0.064 nM.

The assay plate is read in either a Discovery or a RubyStar. Theeu-anti-His H3 is excited at 320 nm and emits at 615 nm to excite theSA-APC which in turn emits at 655 nm. The ratio of SA-APC at 655 nm(excited due to close proximity to the Eu-anti-HisH3 because ofphosphorylation of the peptide) to free Eu-anti-His H3 at 615 nm willgive substrate phosphorylation.

Many of the Examples described herein were tested, and fund to be activecompounds. Table I includes related biological data, which may beinterpreted using the activity gauge below. Selected Examples 2945 and74-370 exhibited an average activity in the Aurora kinase B HTRF assayas follows:

“+” represents an activity (IC₅₀) in the range of 2.5 uM-500 nM;“++” represents an activity (IC₅₀) in the range of 500-100 nM; and“+++” represents an activity (IC₅₀) of less than 100 nM.

Aurora Kinase Cell-based Assay HeLa Cell 24 Hr Ploidy Assay Protocol

The purpose of this assay is to evaluate the ability of selectedindividual compounds to induce Deoxyribonucleic acid (DNA) content(ploidy) in cells through failed cell division. Cell cycle analysis is arapid and efficient way to evaluate the status of DNA content (ploidy)of a given cell. HeLa cells (1×10⁴HeLa cells/well) in 100 ul of media(MEM+10% FBS) were plated in 96-well plates (Packard View) and culturedfor 24 hrs at 37° C. maintained in a 5% CO₂ atmosphere. The followingday, cells were treated for 24 hrs with inhibitor compounds (10 pt. Doseranging from 0.0024-1.25 μmol/L). The compounds were serially diluted inDMSO (0.25% final concentration). The cells were fixed (3.7%Formaldehyde and 1% glutaraldehyde) and permeabilized (1×PBS with 1% BSAand 0.2% Triton X-100) in preparation for nuclear staining. The wellplates were stained for 45 minutes at RT in the dark using Hoechest33342 nuclear stain at 0.5 μg.ml (Stock of 10 mg/ml, Invitrogen, CA, Cat# H3570). The nuclear stain was removed by aspiration and the cells werewashed with wash buffer. A Cellomics Array Scan Vti plate reader wasused to acquire the DNA ploidy data of the cells using Cell Cyclebioapplication. Numbers for each of “valid cell count/well”, “% of 4Ncells” and “% of >4N cells” were calculated with the assistance of anActivity Base 5.1 ca software and dose curves were generated using anXLFit software. With XLFit, final EC₅₀ IP and EC₅₀ transit values, aswell as the Max and Min, were calculated for each curve.

Of the compounds assayed, a number of compounds exhibited activity inthe 24 h cell-ploidy content assay, as provided in the Tables herein.Selected Examples exhibited an average activity in the DNA ploidy assayas follows:

“+” represents an activity (EC₅₀) in the range of 2.5 uM-500 nM;“++” represents an activity (EC₅₀) in the range of 500-100 mM; and“+++” represents an activity (EC₅₀) of less than 100 nM.

HCT116 Xenograft Model

Compounds of the present invention were evaluated in HCT116 xenografts,a human colon carcinoma model. HCT116 cells were chosen to evaluatecompounds of Formulas I-IV in a tumor model based on in vitro datahaving showed a marked increase in polyploidy in the cells in responseto Aurora B inhibition. These cells were grown as subcutaneousxenografts in female HSD (Harlan Sprague Dawley) athymic nude mice. Micewere implanted subcutaneously with 2×10⁶ cells in matrigel on day 0.Treatment was initiated on day 10 with compounds of the invention at theindicated dosage p.o for 2 consecutive-days per week (intermittentschedule, such as 2 days on—5 days off) or 7-days (continuous schedule)per week, for a selected number of weeks. For example, in one study,animals were dosed with selected compound samples BID on an intermittentdosing paradigm of two days on and then 5 days off per week, for fourweeks (four dosing cycles) at 15, 7.5, and 3.75 mg/kg. Tumor growthinhibition and body weights were measured throughout the study andcompared to the vehicle control group. All groups were providednutritional supplements on a daily basis throughout the study tomaintain body weight. Terminal neutrophil counts were taken at the endof this study. Measures were made by ANOVA followed by Scheffe post hoctest using StatView software v5.0.1.

Materials

Tissue Culture: 10 Flasks containing a total of 7.68×10⁸HCT116 tumorcells were harvested for tumor cell implantation. HCT 116 cells werere-suspended to a cell concentration of about 2×10⁷ cells/ml inserum-free McCoys 5A media +50% matrigel. Cell viability was measured tobe about 99.3%.Animals: Female Athymic Nude mice approximately 14 weeks of age (HarlanSprague Dawley) were used for the experiment. Mice were housed five perfilter-capped cage in sterile housing in an environmentally controlledroom (temperature 23±2° C., relative humidity 50±20%) on a 12-hrlight/dark cycle. Animals were fed a commercial rodent chow (Formulation8640; Tek Lab, Madison, Wis.) and received filter-purified tap water adlibitum. Dietary calcium and phosphorus contents were 1.2% and 1.0%,respectively. Mice were individually identified by microchips (BiomedicData Systems, Inc—Seaford, Del.) implanted subcutaneously at least oneweek prior to the study. Mice were implanted with 2×10⁶ cells (100 μl)subcutaneously on the right flank on Day 0. On Day 9, tumor-bearing micewere measured and randomized into five groups (n=10). Treatment of themice with various compound dosages began on Day 10. The duration of thedosing phase of the study was generally four weeks. During the dosingperiod, mouse tumor volumes were measured with a digital caliper andweighed twice per week. Tumor volumes were calculated as follows: TumorVolume (mm³)=[(W²×L)/2] where width (W) is defined as the smaller of the2 measurements and length (L) is defined as the larger of the 2measurements. The following Examples exhibited an inhibition of tumorgrowth in the 116HCT tumor xenograph model: 160 (˜86% inhibition @ 3.75mg/kg 2-day dosing scheduling QD); 165 (˜63% inhibition @ 2.5 mg/kg2-day dosing scheduling BID); and 207 (˜67% inhibition @ 5.0 mg/kg 2-daydosing scheduling QD).

INDICATIONS

The compounds of the invention have Aurora kinase modulatory activity ingeneral, and inhibitory activity in particular. In one embodiment of theinvention, there is provided a method of modulating Aurora kinase enzymein a subject, the method comprising administering to the subject aneffective dosage amount of a compound of a compound of Formulas I-IV. Assuch, the compounds of the invention may be used to treat cellularproliferation disorders, including uncontrolled cell growth and aberrantcell cycle regulation. The compounds are also useful for treatingdisorders related to hyper-proliferation of cells in normal tissue,including without limitation, non-tumor bearing and metastatic tissue.For example, one use may be to protect normal hair follicles fromchemotherapy induced alopecia.

In addition, compounds of the invention are useful for, but not limitedto, the prevention or treatment of cancer and other Aurorakinase-mediated diseases or disorders. For example, compounds of theinvention would be useful for the treatment of various solid andhematologically derived tumors, such as carcinomas, including, withoutlimitation, cancer of the bladder, breast, colon, kidney, liver, lung(including small cell lung cancer), esophagus, gall-bladder, ovary,pancreas, stomach, cervix, thyroid, prostate, and skin (includingsquamous cell carcinoma); hematopoietic tumors of lymphoid lineage(including leukemia, acute lymphocitic leukemia, acute lymphoblasticleukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma);hematopoietic tumors of myeloid lineage (including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia); tumors of mesenchymal origin (including fibrosarcoma andrhabdomyosarcoma, and other sarcomas, e.g. soft tissue and bone); tumorsof the central peripheral nervous system (including astrocytoma,neuroblastoma, glioma and schwannomas); and other tumors (includingmelanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderomapigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi'ssarcoma).

The compounds of the invention are also useful in the treatment ofcancer related indications such as solid tumors, sarcomas (especiallyEwing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas,neuroblastoma, hematopoietic malignancies, including leukemia andlymphoma, tumor-induced pleural or pericardial effusions, and malignantascites.

The compound of the invention may also be used to treatchemotherapy-induced thrombocytopenia, since the compounds may increaseplatelet count be increasing the rate of megakaryocyte maturation.

The compounds would also be useful for treatment of opthalmologicalconditions such as corneal graft rejection, ocular neovascularization,retinal neovascularization including neovascularization following injuryor infection, diabetic retinopathy, retrolental fibroplasia andneovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerativediseases such as gastric ulcer; pathological, but non-malignant,conditions such as hemangiomas, including infantile hemaginomas,angiofibroma of the nasopharynx and avascular necrosis of bone; anddisorders of the female reproductive system such as endometriosis. Thecompounds are also useful for the treatment of edema, and conditions ofvascular hyperpermeability.

The compounds of the invention are also useful in the treatment ofconditions wherein undesired angiogenesis, edema, or stromal depositionoccurs in viral infections such as Herpes simplex, Herpes Zoster, AIDS,Kaposi's sarcoma, protozoan infections and toxoplasmosis, followingtrauma, radiation, stroke, endometriosis, ovarian hyperstimulationsyndrome, systemic lupus, sarcoidosis, synovitis, Crohn's disease,sickle cell anemia, Lyme disease, pemphigoid, Paget's disease,hyperviscosity syndrome, Osler-Weber-Rendu disease, chronicinflammation, chronic occlusive pulmonary disease, asthma, andinflammatory rheumatoid or rheumatic disease. The compounds are alsouseful in the reduction of sub-cutaneous fat and for the treatment ofobesity.

The compounds of the invention are also useful in the treatment ofocular conditions such as ocular and macular edema, ocular neovasculardisease, scleritis, radial keratotomy, uveitis, vitritis, myopia, opticpits, chronic retinal detachment, post-laser complications, glaucoma,conjunctivitis, Stargardt's disease and Eales disease in addition toretinopathy and macular degeneration.

The compounds of the invention are also useful in the treatment ofcardiovascular conditions such as atherosclerosis, restenosis,arteriosclerosis, vascular occlusion and carotid obstructive disease.

Based on the ability to modulate kinases impacting angiogenesis, thecompounds of the invention are also useful in treatment and therapy ofproliferative diseases. Particularly, these compounds can be used forthe treatment of an inflammatory rheumatoid or rheumatic disease,especially of manifestations at the locomotor apparatus, such as variousinflammatory rheumatoid diseases, especially chronic polyarthritisincluding rheumatoid arthritis, juvenile arthritis or psoriasisarthropathy; paraneoplastic syndrome or tumor-induced inflammatorydiseases, turbid efflusions, collagenosis, such as systemic Lupuserythematosus, poly-myositis, dermato-myositis, systemic sclerodermia ormixed collagenosis; postinfectious arthritis (where no living pathogenicorganism can be found at or in the affected part of the body),seronegative spondylarthritis, such as spondylitis ankylosans;vasculitis, sarcoidosis, or arthrosis; or further any combinationsthereof.

The compounds of the invention can also be used as active agents againstsuch disease states as arthritis, atherosclerosis, psoriasis,hemangiomas, myocardial angiogenesis, coronary and cerebral collaterals,ischemic limb angiogenesis, wound healing, peptic ulcer Helicobacterrelated diseases, fractures, cat scratch fever, rubeosis, neovascularglaucoma and retinopathies such as those associated with diabeticretinopathy or macular degeneration. In addition, some of thesecompounds can be used as active agents against solid tumors, malignantascites, hematopoietic cancers and hyperproliferative disorders such asthyroid hyperplasia (especially Grave's disease), and cysts (such ashypervascularity of ovarian stroma, characteristic of polycystic ovariansyndrome (Stein-Leventhal syndrome)) since such diseases require aproliferation of blood vessel cells for growth and/or metastasis.

The compounds of the invention can also be used as active agents againstburns, chronic lung disease, stroke, polyps, anaphylaxis, chronic andallergic inflammation, ovarian hyperstimulation syndrome, braintumor-associated cerebral edema, high-altitude, trauma or hypoxiainduced cerebral or pulmonary edema, ocular and macular edema, ascites,and other diseases where vascular hyperpermeability, efflusions,exudates, protein extravasation, or edema is a manifestation of thedisease. The compounds will also be useful in treating disorders inwhich protein extravasation leads to the deposition of fibrin andextracellular matrix, promoting stromal proliferation (e.g. fibrosis,cirrhosis and carpal tunnel syndrome).

Besides being useful for human treatment, these compounds are useful forveterinary treatment of companion animals, exotic animals and farmanimals, including mammals, rodents, and the like. For example, animalsincluding horses, dogs, and cats may be treated with compounds providedby the invention.

FORMULATIONS

Also embraced within this invention is a class of pharmaceuticalcompositions, also referred to as medicaments, comprising the activecompounds of Formulas I-III in association with one or more non-toxic,pharmaceutically-acceptable excipients and/or carriers, diluents and/oradjuvants (collectively referred to herein as “excipient” materials)and, if desired, other active ingredients. The pharmaceutically activecompounds of this invention can be processed in accordance withconventional methods of pharmacy to produce medicinal agents foradministration to patients, including humans and other mammals.

The compounds of the present invention may be administered to a subjectby any suitable route, preferably in the form of a pharmaceuticalcomposition, adapted to such a route, and in a dose effective for thetreatment intended. The compounds and compositions of the presentinvention may, for example, be administered orally, mucosally,topically, rectally, pulmonarily such as by inhalation spray, orparentally including intravascularly, intravenously, intraperitoneally,subcutaneously, intramuscularly intrasternally and infusion techniques,in dosage unit formulations containing conventional pharmaceuticallyacceptable excipients, including carriers, adjuvants, and vehicles.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of active ingredient from about 1 to 2000 mg, andtypically from about 1 to 500 mg. A suitable daily dose for a human orother mammal may vary widely depending on the condition of the patientand other factors, but, once again, can be determined using routinemethods and practices.

The amount of compounds which are administered and the dosage regimenfor treating a disease condition with the compounds and/or compositionsof this invention depends on a variety of factors, including the age,weight, sex and medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.01 to 500 mg/kg, advantageously between about 0.01 andabout 50 mg/kg, and more advantageously about 0.01 and about 30 mg/kgbody weight may be appropriate. The daily dose can be administered inone to four doses per day.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more “excipients” appropriate to theindicated route of administration. If administered on a per dose basis,the compounds may be admixed with lactose, sucrose, starch powder,cellulose esters of alkanoic acids, cellulose alkyl esters, talc,stearic acid, magnesium stearate, magnesium oxide, sodium and calciumsalts of phosphoric and sulfuric acids, gelatin, acacia gum, sodiumalginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, to form thefinal formulation. For example, the active compound(s) and excipient(s)may be tableted or encapsulated by known and accepted methods forconvenient administration. Examples of suitable formulations include,without limitation, pills, tablets, soft and hard-shell gel capsules,troches, orally-dissolvable forms and delayed or controlled-releaseformulations thereof. Particularly, capsule or tablet formulations maycontain one or more controlled-release agents, such ashydroxypropylmethyl cellulose, as a dispersion with the activecompound(s).

In the case of psoriasis and other skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, pastes, suspensions andthe like) and drops suitable for administration to the eye, ear, ornose. A suitable topical dose of active ingredient of a compound of theinvention is 0.1 mg to 150 mg administered one to four, preferably oneor two times daily. For topical administration, the active ingredientmay comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight ofthe formulation, although it may comprise as much as 10% w/w, butpreferably not more than 5% w/w, and more preferably from 0.1% to 1% ofthe formulation.

When formulated in an ointment, the active ingredients may be employedwith either paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base. If desired, the aqueous phase of the cream base may include,for example at least 30% w/w of a polyhydric alcohol such as propyleneglycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethyleneglycol and mixtures thereof. The topical formulation may desirablyinclude a compound, which enhances absorption or penetration of theactive ingredient through the skin or other affected areas. Examples ofsuch dermal penetration enhancers include DMSO and related analogs.

The compounds of this invention can also be administered by transdermaldevice. Preferably transdermal administration will be accomplished usinga patch either of the reservoir and porous membrane type or of a solidmatrix variety. In either case, the active agent is deliveredcontinuously from the reservoir or microcapsules through a membrane intothe active agent permeable adhesive, which is in contact with the skinor mucosa of the recipient. If the active agent is absorbed through theskin, a controlled and predetermined flow of the active agent isadministered to the recipient. In the case of microcapsules, theencapsulating agent may also function as the membrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase, which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include, for example, Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodiumlauryl sulfate, glyceryl distearate alone or with a wax, or othermaterials well known in the art.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable excipient, especially an aqueous solvent for the activeingredients. The active ingredients are preferably present in suchformulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%and particularly about 1.5% w/w.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the excipients, carriers or diluentsmentioned for use in the formulations for oral administration or byusing other suitable dispersing or wetting agents and suspending agents.The compounds may be dissolved in water, polyethylene glycol, propyleneglycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers.Other adjuvants and modes of administration are well and widely known inthe pharmaceutical art. The active ingredient may also be administeredby injection as a composition with suitable carriers including saline,dextrose, or water, or with cyclodextrin (ie. Captisol), cosolventsolubilization (ie. propylene glycol) or micellar solubilization (ie.Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

Combinations

While the compounds of the invention can be dosed or administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or in conjunction with otheragents. When administered as a combination, the therapeutic agents canbe formulated as separate compositions that are administeredsimultaneously or sequentially at different times, or the therapeuticagents can be given as a single composition.

The phrase “co-therapy” (or “combination-therapy”), in defining use of acompound of the present invention and another pharmaceutical agent, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as in a singlecapsule having a fixed ratio of these active agents or in multiple,separate capsules for each agent.

Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of cancer, such as withradiation therapy or with neoplastic or cytotoxic agents.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof Formulas I-III may also be administered sequentially with knownanticancer or cytotoxic agents when a combination formulation isinappropriate. The invention is not limited in the sequence ofadministration; compounds of the invention may be administered eitherprior to, simultaneous with or after administration of the knownanticancer or cytotoxic agent.

There are large numbers of antineoplastic agents available in commercialuse, in clinical evaluation and in pre-clinical development, which wouldbe selected for treatment of neoplasia by combination drug chemotherapy.Such antineoplastic agents fall into several major categories, namely,antibiotic-type agents, alkylating agents, antimetabolite agents,hormonal agents, immunological agents, interferon-type agents and acategory of miscellaneous agents.

Alternatively, the compounds of the invention may also be used inco-therapies with other anti-neoplastic agents, such as other kinaseinhibitors including angiogenic agents such as VEGFR. inhibitors, p38inhibitors and CDK inhibitors, TNF inhibitors, metallomatrix proteasesinhibitors (MMP), COX-2 inhibitors including celecoxib, rofecoxib,parecoxib, valdecoxib, and etoricoxib, NSAID's, SOD mimics or α_(v)β₃inhibitors.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes, which are obvious to one skilled in the art, are intendedto be within the scope and nature of the invention, which are defined inthe appended claims. All mentioned references, patents, applications andpublications, are hereby incorporated by reference in their entirety, asif here written.

1. A compound of Formula III:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,wherein each of A¹ and A², independently, is CR²; each of A³, A⁴, A⁵ andA⁶, independently, is CR³; each of L¹ and L², independently, is —O—,—NR⁴—, —S—, —C(O)—, —S(O)—, —SO₂— or —CR⁴R⁴—, wherein each R⁴,independently, is H, halo, OH, C₁₋₆alkoxyl, NH—C₁₋₆alkyl, CN orC₁₋₆alkyl; each R¹, independently, is halo, haloalkyl, haloalkoxyl, oxo,CN, OH, SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, —SR⁹, —OR⁹,—NR⁹R⁹, —C(O)R⁹, —COOR^(S), —OC(O)R⁹, —C(O)C(O)R⁹, —C(O)NR⁹R⁹,—NR⁹C(O)R⁹, —NR⁹C(O)NR⁹R⁹, —NR⁹(COOR⁹), —OC(O)NR⁹R⁹, —S(O)₂R⁹, —S(O)₂R⁹,—S(O)₂NR⁹R⁹, —NR⁹S(O)₂NR⁹R⁹, —NR⁹S(O)₂R⁹ or a fully saturated orpartially or fully unsaturated 3-8 membered monocyclic, 6-12 memberedbicyclic, or 7-14 membered tricyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein each ofthe C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of R⁹; eachR², independently, is H, halo, haloalkyl, haloalkoxyl, CN, OH, SH, NO₂,NH₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or —C(O)R⁹; each R³, independently, isH, halo, haloalkyl, haloalkoxyl, CN, OH, SH, NO₂, NH₂, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀ ⁻cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor —C(O)R⁹; R⁶ is R⁹; each R⁹, independently, is H, halo, haloalkyl,haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, SR¹⁰, OR¹⁰, NR⁴R¹⁰, C(O)R¹⁰, COOR¹⁰, C(O)NR⁴R¹⁰,NR⁴C(O)R¹⁰, NR⁴C(O)NR⁴R¹⁰, NR⁴ (COOR¹⁰), S(O)₂R¹⁰, S(O)₂NR⁴R¹⁰,NR⁴S(O)₂R¹⁰, NR⁴S(O)₂NR⁴R¹⁰ or a fully saturated or partially or fullyunsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyland ring of said ring system is optionally substituted independentlywith 1-5 substituents of R¹⁰, halo, haloalkyl, haloalkoxyl, CN, NO₂,NH₂, OH, oxo, C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl; R¹⁰ is H, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a fully saturated or partially or fully unsaturated 3-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀ ⁻cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH, oxo,C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl; and n is 0, 1, 2, 3 or 4;provided that (1) when D′ is a phenyl ring, A¹ is CH and A¹¹s CR², thanR² is not CN—.
 2. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein L¹ is —O—, —S— or —NR⁴—, L² is —NR⁴—and each R⁴, independently, is as defined in claim
 1. 3. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁶ is afully saturated or partially or fully unsaturated 3-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkellyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of R¹⁰, halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH,oxo, C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl;
 4. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each of A³, A⁴, A⁵ andA⁶, independently, is CH.
 5. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each of A¹ and A²,independently, is CR²; L¹ is —O—, —S— or —NR⁴—; L² is —NR⁴—; and R⁶ isphenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyazinyl,triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl,phthalazinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl,thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl,benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, benzodioxolyl,hexahydropyrrolo[1,2-a]pyrazinyl, cyclopropyl, cyclobutyl, azetidinyl,cyclopentyl, cyclohexyl, cycloheptyl or pyranyl, each of which isoptionally substituted independently with 1-5 substituents of R¹⁰, halo,haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH, oxo, C₁₋₆allyl, C₁₋₆alkoxyl,C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, benzyl orphenyl.
 6. The compound of claim 1 having a Formula III:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,wherein A¹ is CR²; A² is CR²; each of A³, A⁴, A⁵ and A⁶, independently,is CR³; L¹ is —O—, —S—, or —NR⁴—; L² is —NR⁴—; each R¹, independently,is halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂, acetyl,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, —SR⁹, —OR⁹, —NR⁹R⁹, —C(O)R⁹, —COOR⁹,—OC(O)R⁹, —C(O)C(O)R⁹, —C(O)NR⁹R⁹, —NR⁹C(O)R⁹, —NR⁹C(O)NR⁹R⁹,—NR⁹(COOR⁹), —OC(O)NR⁹R⁹, —S(O)₂R⁹, —S(O)₂R⁹, —S(O)₂NR⁹R⁹,—NR⁹S(O)₂NR⁹R⁹, —NR⁹S(O)₂R⁹ or a fully saturated or partially or fullyunsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of R⁹; each R², independently, is H, halo, haloalkyl,haloalkoxyl, OH, SH, NO₂, NH₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or —C(O)R⁹; eachR³, independently, is H, halo, haloalkyl, haloalkoxyl, CN, OH, SH, NO₂,NH₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or —C(O)R⁹; each R⁴, independently, isH or C₁₋₆alkyl; R⁶ is a fully saturated or partially or fullyunsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyland ring of said ring system is optionally substituted independentlywith 1-5 substituents of R¹⁰, halo, haloalkyl, haloalkoxyl, CN, NO₂,NH₂, OH, oxo, C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl; each R⁹, independently, is H,halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂, acetyl,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, SR¹⁰, OR¹⁰, NR⁴R¹⁰, C(O)R¹⁰, COOR¹⁹,C(O)NR⁴R¹⁰, NR⁴C(O)R¹⁰, NR⁴C(O)NR⁴R¹⁰, NR⁴ (COOR¹⁹), S(O)₂R¹⁰,S(O)₂NR⁴R¹⁰, NR⁴S(O)₂R¹⁰, NR⁴S(O)₂NR⁴R¹⁹ or a fully saturated orpartially or fully unsaturated 3-8 membered monocyclic or 6-12 memberedbicyclic ring system, said ring system formed of carbon atoms optionallyincluding 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic,said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of R¹⁰, halo,haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH, oxo, C₁₋₆alkyl, C₁₋₆alkoxyl,C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, benzyl orphenyl; R¹⁰ is H, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a fullysaturated or partially or fully unsaturated 3-8 membered monocyclic or6-12 membered bicyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic or 1-6heteroatoms if bicyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH, oxo,C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl; and n is 0, 1, 2, 3 or
 4. 7. Thecompound of claim 1 having a Formula III:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,wherein each of A¹ and A² is CR²; each of A³, A⁴, A⁵ and A⁶,independently, is CR³; each of L¹ and L², independently, is —O—, —NR⁴—,—S—, —C(O)—, —S(O)—, —SO₂— or —CR⁴R⁴—, wherein each R⁴, independently,is H or C₁₋₆alkyl; each R¹, independently, is H, halo, haloalkyl,haloalkoxyl, CN, OH, SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, —SR⁹, —OR⁹,—NR⁹R⁹, —C(O)R⁹, —COOR⁹, —OC(O)R⁹, —C(O)C(O)R⁹, —C(O)NR⁹R⁹, —NR⁹C(O)R⁹,—NR⁹C(O)NR⁹R⁹, —NR⁹(COOR⁹), —OC(O)NR⁹R⁹, —S(O)₂R⁹, —S(O)₂R⁹,—S(O)₂NR⁹R⁹, —NR⁹S(O)₂NR⁹R⁹, —NR⁹S(O)₂R⁹ or a fully saturated orpartially or fully unsaturated 3-8 membered monocyclic, 6-12 memberedbicyclic, or 7-14 membered tricyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein each ofthe C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of R⁹; eachR², independently, is H, halo, haloalkyl, haloalkoxyl, OH, SH, NO₂, NH₂,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or —C(O)R⁹; each R³, independently, isH, halo, haloalkyl, haloalkoxyl, CN, OH, SH, NO₂, NH₂, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor —C(O)R⁹; R⁶ is R⁹; each R⁹, independently, is H, halo, haloalkyl,haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, SR¹⁰, OR¹⁰, NR⁴R¹⁰, C(O)R¹⁰, COOR¹⁹, C(O)NR⁴R¹⁰,NR⁴C(O)R¹⁰, NR⁴C(O)NR⁴R¹⁰, NR⁴ (COOR¹⁰), S(O)₂R¹⁰, S(O)₂NR⁴R¹⁰,NR⁴S(O)₂R¹⁰, NR⁴S(O)₂NR⁴R¹⁰ or a fully saturated or partially or fullyunsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyland ring of said ring system is optionally substituted independentlywith 1-5 substituents of R¹⁰, halo, haloalkyl, haloalkoxyl, CN, NO₂,NH₂, OH, oxo, C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl; R¹⁰ is H, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a fully saturated or partially or fully unsaturated 3-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, haloalkoxyl, CN, NO₂, NH₂, OH, oxo,C₁₋₆alkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, benzyl or phenyl; and n is 0, 1, 2, 3 or
 4. 8. Thecompound of claim 7, or a pharmaceutically acceptable salt thereof,wherein A¹ is CR² and A² is CR²; each of A³, A⁴, A⁵ and A⁶,independently, is CR³; L¹ is —O—, —NR⁴— or —S—; L² is —NR⁴—; each R¹,independently, is H, halo, CF₃, C₂F₅, haloalkoxyl, CN, OH, SH, NO₂, NH₂,acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl,cyclopentyl, hexyl, cyclohexyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, —C(O)R⁹, —COOR⁹, —C(O)NHR⁹, —NHC(O)R⁹, —NHC(O)NHR⁹,—NH(COOR⁹), —S(O)₂R⁹, —S(O)₂R⁹, —S(O)₂NHR⁹, —NHS(O)₂NHR⁹, —NHS(O)₂R⁹ ora ring selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl,pyazinyl, triazinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl,pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl,thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl,isothiazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl,cycloheptyl or pyranyl, said ring optionally substituted independentlywith 1-5 substituents of R⁹; each R², independently, is H, halo, CF₃,CN, NO₂, NH₂, OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, methylamine, dimethylamine, ethylamine, diethylamine,propylamine or isopropylamine; each R³, independently, is H, halo, CF₃,CN, NO₂, NH₂, OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, methylamine, dimethylamine, ethylamine, diethylamine,propylamine or isopropylamine; each R⁴, independently, is H orC₁₋₆alkyl; and R⁶ is phenyl, naphthyl, pyridyl, pyrimidinyl,pyridazinyl, pyazinyl, triazinyl, quinolinyl, dihydroquinolinyl,tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,quinazolinyl, isoquinazolinyl, phthalazinyl, thiophenyl, furyl,tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl,triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, benzothiazolyl,oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, isoxazolyl,isothiazolyl, indolyl, azaindolyl, 2,3-dihydroindolyl, isoindolyl,indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,imidazo-pyridinyl, purinyl, benzotriazolyl, oxazolinyl, isoxazolinyl,thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl, dioxozinyl, 2,3-dihydro-1,4-benzoxazinyl,1,3-benzodioxolyl, benzodioxolyl, hexahydropyrrolo[1,2-a]pyrazinyl,cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl,cycloheptyl or pyranyl, each of which is optionally substitutedindependently with 1-5 substituents of R¹⁰, halo, haloalkyl,haloalkoxyl, CN, NO₂, NH₂, OH, oxo, C₁₋₆alkyl, C₁₋₆alkoxyl,C₃₋₆cycloalkyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, benzyl orphenyl.
 9. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, selected from,4-((4-((4-(4-methyl-1,3-thiazol-2-yl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;4-((4-((4-(4-(methyloxy)phenyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;′4-(1-methyl-1H-indol-2-yl)-N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-1-phthalazinamine;′N-(4-((7-(methyloxy)-1,5-naphthyridin-4-yl)oxy)phenyl)-4-(4-(trifluoromethyl)phenyl)-1-phthalazinamine;′4-((4-((4-(4-(trifluoromethyl)phenyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;4-((4-((4-(4-(trifluoromethyl)phenyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;4-((4-((4-(4-chlorophenyl)-1-phthalazinyl)amino)phenyl)thio)-7-quinolinecarbonitrile;′N-(4-((6-(methyloxy)-4-quinolinyl)thio)phenyl)-4-phenyl-1-phthalazinamine;N-(4-((6,7-bis(methyloxy)-4-quinolinyl)oxy)phenyl)-4-(3,4-dimethylphenyl)-1-phthalazinamine;N-(4-((6,7-bis(methyloxy)-4-quinolinyl)oxy)phenyl)-4-(1-piperidinyl)-1-phthalazinamine;N-(4-((6,7-bis(methyloxy)-4-quinolinyl)oxy)-3-fluorophenyl)-4-(2-thienyl)-1-phthalazinamine;N-(4-((6,7-bis(methyloxy)-4-quinolinyl)oxy)-3-fluorophenyl)-4-(3,5-dimethyl-1H-pyrazol-1-yl)-1-phthalazinamine;4-((4-((4-(4-methyl-1,3-thiazol-2-yl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;4-((4-((4-(5-fluoro-2-(methyloxy)phenyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;4-((4-((4-(4-methylphenyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;N-(4-((6,7-bis(methyloxy)-4-quinolinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine;N-(4-((7-(methyloxy)-4-quinolinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine;4-((4-((4-(3-hydroxyphenyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;4-((4-((4-(4-methyl-1-piperazinyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;4-((4-((4-(4-methyl-1,3-thiazol-2-yl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarboxamide;4-((4-((4-(5-fluoro-2-(methyloxy)phenyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarboxamide;4-(6-(methyloxy)-2-pyridinyl)-N-(4-(7-(methyloxy)-4-quinolinyl)oxy)phenyl)-1-phthalazinamine;N-(4-((6,7-bis(methyloxy)-4-quinolinyl)oxy)phenyl)-4-(6-(methyloxy)-2-pyridinyl)-1-phthalazinamine;4-((4-((4-(6-(methyloxy)-2-pyridinyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;N-(4-((6,7-bis(methyloxy)-4-quinolinyl)thio)phenyl)-4-phenyl-1-phthalazinamine;4-((4-((4-phenyl-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;N-(4-((6,7-bis(methyloxy)-4-quinolinyl)oxy)phenyl)-4-(4-(1,1-dimethylethyl)phenyl)-1-phthalazinamine;(6-(4-((4-((6,7-bis(methyloxy)-4-quinolinyl)oxy)phenyl)amino)-1-phthalazinyl)-2-pyridinyl)methanol;(6-(4-((4-((6,7-bis(methyloxy)-4-quinolinyl)oxy)phenyl)amino)-1-phthalazinyl)-2-pyridinyl)methylacetate;N-(3-fluoro-4-(4-quinolinyloxy)phenyl)-4-phenyl-1-phthalazinamine;N-(4-((6,7-bis(methyloxy)-4-quinolinyl)oxy)phenyl)-4-(4-methyl-2-pyridinyl)-1-phthalazinamine;N-(4-((7-(methyloxy)-4-quinolinyl)oxy)phenyl)-4-(4-methyl-2-pyridinyl)-1-phthalazinamine;4-((4-((4-(2-(methyloxy)phenyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;4-((4-((4-(5-methyl-2-pyridinyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;N-(4-((7-bromo-4-quinolinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine;N-(4-((6-bromo-4-quinolinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine;4-((4-((4-(4-(methyloxy)phenyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;4-((4-((4-(4-(trifluoromethyl)phenyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;N-(4-((6,7-bis(methyloxy)-4-quinolinyl)oxy)phenyl)-4-(6-methyl-2-pyridinyl)-1-phthalazinamine;N-(3-fluoro-4-(4-quinolinyloxy)phenyl)-4-(4-methylphenyl)-1-phthalazinamine;4-((4-((4-(5-methyl-2-thienyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;N-(4-((3-fluoro-7-(methyloxy)-4-quinolinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine;4-((4-((4-(4-methyl-2-thienyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;4-(5-(4-phenylphthalazin-1-ylamino)pyridin-2-yloxy)quinoline-7-carbonitrile;4-((4-((4-(3-methyl-2-thienyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;N-(3-fluoro-4-(4-quinolinyloxy)phenyl)-4-(6-(methyloxy)-2-pyridinyl)-1-phthalazinamine;N-(4-((3-fluoro-7-(methyloxy)-4-quinolinyl)oxy)phenyl)-4-(4-(trifluoromethyl)phenyl)-1-phthalazinamine;N-(4-((7-(4-morpholinyl)-4-quinolinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine;4-((4-((4-phenyl-1-phthalazinyl)amino)phenyl)thio)-7-quinolinecarbonitrile;7-(methyloxy)-4-((4-((4-(4-methylphenyl)-1-phthalazinyl)amino)phenyl)oxy)-6-quinolinecarboxamide;4-((4-((4-(4-cyanophenyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;7-(methyloxy)-4-((4-((4-phenyl-1-phthalazinyl)amino)phenyl)oxy)-6-quinolinecarboxamide;4-((4-((4-(4-chloro-3-cyanophenyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;N-(4-((6-(methyloxy)-4-quinolinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine;4-(4-chlorophenyl)-N-(4-((6-(methyloxy)-4-quinolinyl)oxy)phenyl)-1-phthalazinamine;4-((4-((4-(4-chlorophenyl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;4-(4-chlorophenyl)-N-(3-fluoro-4-(4-quinolinyloxy)phenyl)-1-phthalazinamine;4-((4-((4-(4-chlorophenyl)-1-phthalazinyl)amino)phenyl)thio)-7-quinolinecarbonitrile;N-(4-((6-(4-morpholinyl)-4-quinolinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine;N-(4-((6-(methyloxy)-4-quinolinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine;N-(4-(5,7-difluoroquinolin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine;4-((4-((4-(4,5-dimethyl-1,3-thiazol-2-yl)-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinecarbonitrile;4-(5-chloro-2-pyridinyl)-N-(4-((6-(methyloxy)-4-quinolinyl)oxy)phenyl)-1-phthalazinamine;N-(4-((6-(methyloxy)-4-quinolinyl)thio)phenyl)-4-phenyl-1-phthalazinamine;N-(4-((6-(1-methyl-1H-pyrazol-4-yl)-4-quinolinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine;N-(4-((4-((4-phenyl-1-phthalazinyl)amino)phenyl)oxy)-6-quinolinyl)acetamide;4-phenyl-N-(4-(4-quinolinylthio)phenyl)-1-phthalazinamine;N-(4-((5,7-difluoro-4-quinolinyl)thio)phenyl)-4-phenyl-1-phthalazinamine;4-(4-chlorophenyl)-N-(4-(6-methoxyquinolin-4-ylthio)phenyl)phthalazin-1-amine;4-phenyl-N-(4-((7-(1H-pyrazol-4-yl)-4-quinolinyl)oxy)phenyl)-1-phthalazinamine;6-(methyloxy)-4-((4-((4-phenyl-1-phthalazinyl)amino)phenyl)oxy)-7-quinolinol;4-(4-chlorophenyl)-N-(4-((7-((2-(methyloxy)ethyl)oxy)-4-quinolinyl)thio)phenyl)-1-phthalazinamine;4-(4-chlorophenyl)-N-(4-((6-((2-(methyloxy)ethyl)oxy)-4-quinolinyl)thio)phenyl)-1-phthalazinamine;4-((4-((4-(4-chlorophenyl)-1-phthalazinyl)amino)phenyl)thio)-6-quinolinol;4-(4-chlorophenyl)-N-(4-((6-((2-((2-(methyloxy)ethyl)oxy)ethyl)oxy)-4-quinolinyl)thio)phenyl)-1-phthalazinamine;4-(4-chlorophenyl)-N-(4-((6-((2-(methylsulfonyl)ethyl)oxy)-4-quinolinyl)thio)phenyl)-1-phthalazinamine;4-(4-chlorophenyl)-N-(4-((5,7-dimethoxy-4-quinolinyl)oxy)phenyl)-1-phthalazinamine;4-(4-chlorophenyl)-N-(4-((5,7-dimethoxy-4-quinolinyl)sulfanyl)phenyl)-1-phthalazinamine;4-(4-chlorophenyl)-N-(4-((7-fluoro-5-methoxy-4-quinolinyl)oxy)phenyl)-1-phthalazinamine;4-(4-chlorophenyl)-N-(4-((7-fluoro-5-methoxy-4-quinolinyl)sulfanyl)phenyl)-1-phthalazinamine;N-(4-((5,7-dimethoxy-4-quinolinyl)sulfanyl)phenyl)-4-(4-methyl-2-thiophenyl)-1-phthalazinamine;N-(4-(7-fluoro-5-methoxy-4-quinolinyl)sulfanyl)phenyl)-4-(4-methyl-2-thiophenyl)-1-phthalazinamine;N-(4-((5,7-dimethoxy-4-quinolinyl)oxy)phenyl)-4-(4-methyl-2-thiophenyl)-1-phthalazinamine;N-(4-((7-fluoro-5-methoxy-4-quinolinyl)oxy)phenyl)-4-(4-methyl-2-thiophenyl)-1-phthalazinamine;7-(methyloxy)-4-((4-((4-phenyl-1-phthalazinyl)amino)phenyl)oxy)-6-quinolinecarbonitrile;N-(4-((6-(methyloxy)-7-((2-(methyloxy)ethyl)oxy)-4-quinolinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine;4-(4-chlorophenyl)-N-(4-((7-fluoro-4-quinolinyl)oxy)phenyl)-1-phthalazinamine;N-(4-((6-amino-4-quinolinyl)thio)phenyl)-4-phenyl-1-phthalazinamine;4-phenyl-N-(4-((7-((trifluoromethyl)oxy)-4-quinolinyl)oxy)phenyl)-1-phthalazinamine;4-phenyl-N-(4-((7-((trifluoromethyl)oxy)-4-quinolinyl)thio)phenyl)-1-phthalazinamine;4-(1,3-benzodioxol-5-yl)-N-(4-(4-quinolinylthio)phenyl)-1-phthalazinamine;4-((4-((4-(4-(methyloxy)-1-piperidinyl)-1-phthalazinyl)amino)phenyl)thio)-7-quinolinecarbonitrile;4-(3-amino-4-methylphenyl)-N-(4-(4-quinolinyloxy)phenyl)-1-phthalazinamine;4-phenyl-N-(4-((6-((trifluoromethyl)oxy)-4-quinolinyl)thio)phenyl)-1-phthalazinamine;4-(4-methyl-2-thienyl)-N-(4-((6-((trifluoromethyl)oxy)-4-quinolinyl)thio)phenyl)-1-phthalazinamine;4-(4-chlorophenyl)-N-(4-((6-((trifluoromethyl)oxy)-4-quinolinyl)oxy)phenyl)-1-phthalazinamine;4-(4-methyl-2-thienyl)-N-(4-((6-((trifluoromethyl)oxy)-4-quinolinyl)oxy)phenyl)-1-phthalazinamine;4-((4-((4-phenyl-1-phthalazinyl)amino)phenyl)oxy)-6-quinolinecarbonitrile;4-(4-chlorophenyl)-N-(4-(1-(7-(methyloxy)-4-quinolinyl)ethyl)phenyl)-1-phthalazinamine;(4-((4-(4-chlorophenyl)-1-phthalazinyl)amino)phenyl)(7-(methyloxy)-4-quinolinyl)methanol;and(4-((4-(4-chlorophenyl)-1-phthalazinyl)amino)phenyl)(7-(methyloxy)-4-quinolinyl)methanone.10. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and an effective dosage amount of the compound ofclaim
 1. 11. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and an effective dosage amount of a compound ofclaim
 7. 12. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and an effective dosage amount of a compound ofclaim 9.